The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications
Yumeng Gao, Jun Zhang
Acta Pharmaceutica Sinica B, doi:10.1016/j.apsb.2025.07.001
The main protease (M pro ) of SARS-CoV-2 plays a pivotal role in viral replication and immune evasion. Accumulating evidence highlights its significant role in suppressing innate immunity. In this review, we provide a comprehensive overview of how M pro modulates host innate immune responses, including its interference with retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathways, inhibition of interferon production, and disruption of inflammasome activities. As a protease, M pro cleaves a variety of host proteins to attenuate antiviral innate immunity, a process dependent on its catalytic dyad (Cys145 -His41), which is crucial for its proteolytic activity. Meanwhile, M pro also exerts innate immune regulatory functions in a protease-independent manner. Notably, inhibitors targeting M pro have demonstrated efficacy in restoring immune functions and suppressing viral replication, offering potential therapeutic strategies against SARS-CoV-2 infection.
SARS-CoV-2 main protease modulates host innate immunity
Author contributions Jun Zhang and Yumeng Gao discussed and determined the theme together. Yumeng Gao wrote the review, and Jun Zhang revised the review.
Conflicts of interest The authors declare no conflicts of interest.
References
Almutairi, Malik, Alonazi, Khan, Alhomida et al., Expression, purification, and biophysical characterization of recombinant MERS-CoV main (Mpro) protease, Int J Biol Macromol
Alugubelli, Xiao, Khatua, Kumar, Sun et al., Discovery of first-in-class PROTAC degraders of SARS-CoV-2 main protease, J Med Chem
Bhardwaj, Singh, Sharma, Rajendran, Purohit et al., Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors, J Biomol Struct Dyn
Bortolotti, Gentili, Rizzo, Schiuma, Beltrami et al., TLR3 and TLR7 RNA sensor activation during SARS-CoV-2 infection, Microorganisms
Cantuti-Castelvetri, Ojha, Pedro, Djannatian, Franz et al., Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity, Science
Cao, Wang, Lu, Huang, Yang et al., Oral simnotrelvir for adult patients with mild-to-moderate Covid-19, N Engl J Med
Chen, Chen, Lin, Chen, Tsao et al., NLRP12 regulates anti-viral RIG-I activation via interaction with TRIM25, Cell Host Microbe
Chen, Li, Guo, Xu, Zhou et al., SARS-CoV-2 nsp5 exhibits stronger catalytic activity and interferon antagonism than its SARS-CoV ortholog, J Virol
Choi, Wan, Wong, Chan, Chu et al., Comparative effectiveness of combination therapy with nirmatrelvirritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir-ritonavir in patients hospitalised with COVID-19: a target trial emulation study, Lancet Infect Dis
Chow, Gale, Jr, Loo, RIG-I and other RNA sensors in antiviral immunity, Annu Rev Immunol
Chu, Shuai, Qiao, Yoon, Zhang et al., An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anticoronavirus efficacy in vivo, Res Sq,
doi:10.21203/rs.3.rs-5454588/v1Clausen, Sandoval, Spliid, Pihl, Perrett et al., SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2, Cell
Dewe, Fuller, Lentini, Kellner, Fu, TRMT1-catalyzed tRNA modifications are required for redox homeostasis to ensure proper cellular proliferation and oxidative stress survival, Mol Cell Biol
Duan, Zhou, Liu, Iketani, Lin et al., Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir, Nature
Dunphy, Flannery, Almine, Connolly, Paulus et al., Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signaling after nuclear DNA damage, Mol Cell
Essalmani, Jain, Resiga, ´o, Evagelidis et al., Distinctive roles of furin and TMPRSS2 in SARS-CoV-2 infectivity, J Virol
Fani, Teimoori, Ghafari, Comparison of the COVID-2019 (SARS-CoV-2) pathogenesis with SARS-CoV and MERS-CoV infections, Future Virol
Fatima, Geethakumari, Ahmed, Biswas, A potential allosteric inhibitor of SARS-CoV-2 main protease (M pro ) identified through metastable state analysis, Front Mol Biosci
Fiaschi, Biba, Varasi, Bartolini, Paletti et al., In vitro combinatorial activity of direct acting antivirals and monoclonal antibodies against the ancestral B.1 and BQ.1.1 SARS-CoV-2 viral variants, Viruses
Fu, Wang, Zheng, Yi, Li et al., SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response, Cell Mol Immunol
Fung, Siu, Lin, Yeung, Jin, SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3, Int J Biol Sci
Gidari, Sabbatini, Schiaroli, Bastianelli, Pierucci et al., Synergistic activity of remdesivir-nirmatrelvir combination on a SARS-CoV-2 in vitro model and a case report, Viruses
Grin, Baid, De Jesus, Kozarac, Bell et al., SARS-CoV-2 3CLpro (main protease) regulates caspase activation of gasdermin-D/E pores leading to secretion and extracellular activity of 3CLpro, Cell Rep
Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19, N Engl J Med
Hirsch, Kreuzberger, Skoetz, Monsef, Kluge et al., Efficacy and safety of antiviral therapies for the treatment of persistent COVID-19 in immunocompromised patients since the Omicron surge: a systematic review, J Antimicrob Chemother
Hoffmann, Kleine-Weber, Schroeder, Kru ¨ger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Honda, Takaoka, Taniguchi, Type I inteferon gene induction by the interferon regulatory factor family of transcription factors, Immunity
Hopfner, Hornung, Molecular mechanisms and cellular functions of cGAS-STING signalling, Nat Rev Mol Cell Biol
Iketani, Mohri, Culbertson, Hong, Duan et al., Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir, Nature
Ip, Chu, Chan, Leung, Abdullah et al., Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance, EBioMedicine
Jiang, Han, Xu, Zhang, Peng et al., Olgotrelvir as a single-agent treatment of nonhospitalized patients with Covid-19, NEJM Evid
Jiang, Li, Jiang, Jiang, Qin et al., Early use of oral antiviral drugs and the risk of post COVID-19 syndrome: a systematic review and network meta-analysis, J Infect
Jin, Du, Xu, Deng, Liu et al., Structure of M pro from SARS-CoV-2 and discovery of its inhibitors, Nature
Ju, Wang, Wang, Ren, Yu et al., SARS-CoV-2 main protease cleaves MAGED2 to antagonize host antiviral defense, mBio
Junqueira, Crespo, Ranjbar, De Lacerda, Lewandrowski et al., FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation, Nature
Kim, Sze, Liu, Lam, The stress granule protein G3BP1 binds viral dsRNA and RIG-I to enhance interferon-ß response, J Biol Chem
Kiso, Yamayoshi, Iida, Furusawa, Hirata et al., In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir, Nat Commun
Kneller, Phillips, Neill, Jedrzejczak, Stols et al., Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography, Nat Commun
Koudelka, Boger, Henkel, Scho ¨nherr R, Krantz et al., N-Terminomics for the identification of in vitro substrates and cleavage site specificity of the SARS-CoV-2 main protease, Proteomics
Kumar, Grams, Bloom, Toth, Signaling pathway reporter screen with SARS-CoV-2 proteins identifies nsp5 as a repressor of p53 activity, Viruses
Lamb, Nirmatrelvir plus ritonavir: first approval, Drugs
Lavigne, Helynck, Rigolet, Boudria-Souilah, Nowakowski et al., SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction, Nucleic Acids Res
Le, Chang, Lu, Chen, Su et al., Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants, Antiviral Res
Lear, Boudreau, Lockwood, Chu, Camarco et al., E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro, J Biol Chem
Lee, Kenward, Worrall, Vuckovic, Gentile et al., X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation, Nat Commun
Lee, Worrall, Vuckovic, Rosell, Gentile et al., Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site, Nat Commun
Lei, Dong, Ma, Xiao, Tian, Activation and evasion of type I interferon responses by SARS-CoV-2, Nat Commun
Lewandowski, Zhang, Tan, Jaskolka-Brown, Kohaal et al., Distal protein-protein interactions contribute to nirmatrelvir resistance, Nat Commun
Li, Liao, Wang, Tan, Luo et al., The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway, Virus Res
Li, Qiao, You, Zong, Peng et al., SARS-CoV-2 Nsp5 activates NF-κB pathway by upregulating SUMOylation of MAVS, Front Immunol
Li, Sun, Lei, Liu, Chen et al., Methyl rosmarinate is an allosteric inhibitor of SARS-CoV-2 3 CL protease as a potential candidate against SARS-cov-2 infection, Antiviral Res
Li, Wang, Wang, Li, Chen et al., Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity, Signal Transduct Targeted Ther
Li, Yu, Huang, Chen, Ren et al., SARS-CoV-2 SUD2 and Nsp5 conspire to boost apoptosis of respiratory epithelial cells via an augmented interaction with the G-quadruplex of BclII, mBio
Liang, Bao, Yang, Liu, Sun et al., SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy, Signal Transduct Targeted Ther
Liang, Gu, Zhu, Yan, Schenten et al., The main protease of SARS-CoV-2 downregulates innate immunity via a translational repression, Signal Transduct Targeted Ther
Lin, Zeng, Duan, Yang, Ma et al., Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants, Commun Biol
Liu, Qin, Rao, Ngo, Feng et al., SARS-CoV-2 Nsp5 demonstrates two distinct mechanisms targeting RIG-I and MAVS to evade the innate immune response, mBio
Lu, Zhang, Mao, Chen, Zhan et al., Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial, eClinicalMedicine
Lu, Zhou, SARS-CoV-2 main protease Nsp5 cleaves and inactivates human tRNA methyltransferase TRMT1, J Mol Cell Biol
Mao, Shaabani, Zhang, Xu, Argent, Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19, Med
Martia ´n ˜ez-Vendrell, Van Kasteren, Myeni, Kikkert, HCoV-229E Mpro suppresses RLR-mediated innate immune signalling through cleavage of NEMO and through other mechanisms, Int J Mol Sci
Mcgovern-Gooch, Mani, Gotchev, Ardzinski, Kowalski et al., Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pancoronavirus activity, Antivir Res
Meyers, Ramanathan, Shanderson, Beck, Donohue et al., The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation, PLoS Pathog
Miczi, Golda, Kunkli, Nagy, T} Ozse ´r et al., Identification of host cellular protein substrates of SARS-COV-2 main protease, IJMS
Miorin, Kehrer, Sanchez-Aparicio, Zhang, Cohen et al., SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling, Proc Natl Acad Sci U S A
Ml, Samples, Dyer, Monta ´n, Vm et al., Metabolomic analysis and antiviral screening of a marine algae library yield jobosic acid (2,5dimethyltetradecanoic acid) as a selective inhibitor of SARS-CoV-2, J Nat Prod
Moon, Porges, Roberts, Bacon, A combination of nirmatrelvir and ombitasvir boosts inhibition of SARS-CoV-2 replication, Antiviral Res
Moustaqil, Ollivier, Chiu, Van Tol, Rudolffi-Soto et al., SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species, Emerg Microb Infect
Mukae, Yotsuyanagi, Ohmagari, Doi, Imamura et al., A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part, Antimicrob Agents Chemother
Naik, Lee, Veronese, Ma, Toth, Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 is not required for NSP5mediated inhibition of type I interferon signaling pathway, Microbiol Spectr
Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19, Science
Pan, Shen, Yu, Ge, Chen et al., SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation, Nat Commun
Park, Lee, Jeong, Kweon, Shin et al., A gain-of-function cleavage of TonEBP by coronavirus NSP5 to suppress IFN-ß expression, Cells
Paunovic, Vucicevic, Marjanovic, Perovic, Ristic et al., Autophagy receptor p62 regulates SARS-CoV-2-induced inflammation in COVID-19, Cells
Plane `s R, Bert, Tairi, Benmohamed, Bahraoui, SARS-CoV-2 envelope (E) protein binds and activates TLR2 pathway: a novel molecular target for COVID-19 interventions, Viruses
Plane `s R, Pinilla, Santoni, Hessel, Passemar et al., Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells, Mol Cell
Redondo, Zaldı ´var-Lo ´pez, Garrido, Montoya, SARS-CoV-2 accessory proteins in viral pathogenesis: knowns and unknowns, Front Immunol
Rehwinkel, Gack, RIG-I-like receptors: their regulation and roles in RNA sensing, Nat Rev Immunol
Rivas, Aaronson, Munoz-Fontela, Dual role of p53 in innate antiviral immunity, Viruses
Rothman, Stewart, Mourad, Boulware, Mccarthy et al., SARS-CoV-2 viral dynamics in a placebo-controlled phase 2 study of patients infected with the SARS-CoV-2 Omicron variant and treated with pomotrelvir, Microbiol Spectr
Rubin, The latest research about paxlovid: effectiveness, access, and possible long COVID benefits, JAMA
Rui, Su, Shen, Hu, Huang et al., Unique and complementary suppression of cGAS-STING and RNA sensingtriggered innate immune responses by SARS-CoV-2 proteins, Signal Transduct Targeted Ther
Sang, Wang, Zhou, Xu, Warshel, A chemical strategy for the degradation of the main protease of SARS-CoV-2 in cells, J Am Chem Soc
Sasaki, Sugi, Iida, Hirata, Kusakabe et al., Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model, EBioMedicine
Schneider, Chevillotte, Rice, Interferon-stimulated genes: a complex web of host defenses, Annu Rev Immunol
Scott, Lacasse, Blom, Tonner, Blom, Predicted coronavirus Nsp5 protease cleavage sites in the human proteome, BMC Genom Data
Shemesh, Aktepe, Deerain, Mcauley, Audsley et al., SARS-CoV-2 suppresses IFNß production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon, PLoS Pathog
Shen, Guo, Li, Zhang, Tang et al., SARS-CoV-2 and oncolytic EV-D68-encoded proteases differentially regulate pyroptosis, J Virol
Shi, Lv, Wang, Xu, Xu et al., Coronaviruses Nsp5 antagonizes porcine Gasdermin D-mediated pyroptosis by cleaving pore-forming p30 fragment, mBio
Shi, Zhao, Wang, Shi, Wang et al., Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death, Nature
Shimizu, Sonoyama, Fukuhara, Kuwata, Matsuo et al., A phase 1 study of ensitrelvir fumaric acid tablets evaluating the safety, pharmacokinetics and food effect in healthy adult populations, Clin Drug Invest
Shin, Mukherjee, Grewe, Bojkova, Baek et al., Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity, Nature
Shteinfer-Kuzmine, Verma, Bornshten, Chetrit, Ben-Ya'acov et al., Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release, Apoptosis
Singh, Bhardwaj, Purohit, Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: an in-silico approach, Comput Biol Med
Singh, Purohit, Multi-target approach against SARS-CoV-2 by stone apple molecules: a master key to drug design, Phytother Res
Song, Kim, Kwak, Lee, Park et al., The N-terminal peptide of the main protease of SARS-CoV-2, targeting dimer interface, inhibits its proteolytic activity, BMB Rep
Song, Wang, Abbas, Li, Cui et al., The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes, J Biol Chem
Tan, Yang, Wang, Peng, Li et al., De novo discovery of a noncovalent cell-penetrating bicyclic peptide inhibitor targeting SARS-CoV-2 main protease, J Med Chem
Thorne, Reuschl, Zuliani-Alvarez, Whelan, Turner et al., SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation, EMBO J
Ting, Duncan, Lei, How the non-inflammasome NLRs function in the innate immune system, Science
Tuladhar, Kanneganti, NLRP12 in innate immunity and inflammation, Mol Aspects Med
Tuttle, Allais, Allerton, Anderson, Arcari et al., Discovery of nirmatrelvir (PF-07321332): a potent, orally active inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) main protease, J Med Chem
Wang, Chen, Zhang, Deng, Lian et al., CD147spike protein is a novel route for SARS-CoV-2 infection to host cells, Signal Transduct Targeted Ther
Wang, Gotchev, Fan, Vega, Mani et al., Rational design of macrocyclic noncovalent inhibitors of SARS-CoV-2 Mpro from a DNA-encoded chemical library screening hit that demonstrate potent inhibition against pancoronavirus homologues and nirmatrelvir-resistant variants, J Med Chem
Wang, Li, Cai, Lin, Ou et al., Antiviral efficacy of RAY1216 monotherapy and combination therapy with ritonavir in patients with COVID-19: a phase 2, single centre, randomised, double-blind, placebo-controlled trial, eClinicalMedicine
Westberg, Su, Zou, Huang, Rustagi et al., An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations, Sci Transl Med
Wu, Li, Tian, Yan, Pan et al., Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3, PLoS Pathog
Wu, Ma, Zhuang, Cai, Zhao et al., Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling, Signal Transduct Targeted Ther
Wu, Shi, Pan, Wu, Hou et al., SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO, Cell Rep
Wu, Wang, Zeng, Huang, Xu et al., Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus, Virus Res
Wu, Zhao, Yu, Chen, Song, A new coronavirus associated with human respiratory disease in China, Nature
Xia, Cao, Xie, Zhang, Chen et al., Evasion of type I interferon by SARS-CoV-2, Cell Rep
Xiong, Huang, Yang, Fu, Fu et al., The substrate selectivity of papain-like proteases from human-infecting coronaviruses correlates with innate immune suppression, Sci Signal
Xiong, Su, Zhao, Xie, Shao et al., What coronavirus 3C-like protease tells us: from structure, substrate selectivity, to inhibitor design, Med Res Rev
Yamada, Sato, Sotoyama, Orba, Sawa et al., RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells, Nat Immunol
Yang, Fu, Gou, Lin, Wu et al., Molecular mechanismdriven discovery of novel small molecule inhibitors against drugresistant SARS-CoV-2 M pro variants, J Chem Inf Model
Yang, Geng, Harrison, Wang, Differential roles of RIG-I like receptors in SARS-CoV-2 infection, Mil Med Res
Yang, Lee, Gao, Song, Jang et al., Miniaturized modular click chemistry-enabled rapid discovery of unique SARS-CoV-2 M pro inhibitors with robust potency and drug-like profile, Adv Sci (Weinh)
Yang, Rao, Structural biology of SARS-CoV-2 and implications for therapeutic development, Nat Rev Microbiol
Yang, Yang, Yao, Ye, Xu et al., A first-inhuman phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects, Eur J Pharmaceut Sci
Ye, Fan, Zhao, Wu, Liu et al., Potential herb-drug interactions between anti-COVID-19 drugs and traditional Chinese medicine, Acta Pharm Sin B
Yin, Riva, Pu, Martin-Sancho, Kanamune et al., MDA5 governs the innate immune response to SARS-CoV-2 in lung epithelial cells, Cell Rep
Yotsuyanagi, Ohmagari, Doi, Yamato, Bac et al., Efficacy and safety of 5-day oral ensitrelvir for patients with mild to moderate COVID-19, JAMA Netw Open
Yu, Zheng, Chen, Lv, Zhu et al., Efficacy and safety of Huashi Baidu granule plus Nirmatrelvir-Ritonavir combination therapy in patients with high-risk factors infected with Omicron (B.1.1.529): a multi-arm single-center, open-label, randomized controlled trial, Phytomedicine
Yuen, Lam, Wong, Mak, Wang et al., SARS-CoV-2 nsp 13, nsp14, nsp15 and orf6 function as potent interferon antagonists, Emerg Microb Infect
Zhan, Lin, Liang, Sun, Li et al., Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial, eClinicalMedicine
Zhang, Kandwal, Fayne, Stevenson, MERS-CoV-nsp5 expression in human epithelial BEAS 2b cells attenuates type I interferon production by inhibiting IRF3 nuclear translocation, Cell Mol Life Sci
Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science
Zhang, Liu, Xu, Li, Lu, Cleavage of the selective autophagy receptor SQSTM1/p62 by the SARS-CoV-2 main protease NSP5 prevents the autophagic degradation of viral membrane proteins, Mol Biomed
Zhang, Ma, Wu, Shi, Zhang et al., SARS-CoV-2 3C-like protease antagonizes interferon-beta production by facilitating the degradation of IRF3, Cytokine
Zhang, Wang, Cheng, Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1, Proc Natl Acad Sci U S A
Zhang, Zhang, Zhang, Zhang, Liu et al., Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase, Virol Sin
Zhang, Zhou, Chen, Mao, Tang et al., Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171, Antimicrob Agents Chemother
Zhao, Fang, Zhang, Zhang, Zhao et al., Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332, Protein Cell
Zheng, Deng, Han, Zhuang, Xu et al., SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules, Signal Transduct Targeted Ther
Zhong, Peng, Du, Chen, Feng et al., Oridonin inhibits SARS-CoV-2 by targeting its 3C-like protease, Small Sci
Zhou, Liu, Pathak, Wang, Jeong et al., Ubiquitin ligase parkin regulates the stability of SARS-CoV-2 main protease and suppresses viral replication, ACS Infect Dis
Zhou, Zhang, Lei, Xiao, Jiao et al., Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection, Signal Transduct Targeted Ther
DOI record:
{
"DOI": "10.1016/j.apsb.2025.07.001",
"ISSN": [
"2211-3835"
],
"URL": "http://dx.doi.org/10.1016/j.apsb.2025.07.001",
"alternative-id": [
"S2211383525004563"
],
"assertion": [
{
"label": "This article is maintained by",
"name": "publisher",
"value": "Elsevier"
},
{
"label": "Article Title",
"name": "articletitle",
"value": "The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications"
},
{
"label": "Journal Title",
"name": "journaltitle",
"value": "Acta Pharmaceutica Sinica B"
},
{
"label": "CrossRef DOI link to publisher maintained version",
"name": "articlelink",
"value": "https://doi.org/10.1016/j.apsb.2025.07.001"
},
{
"label": "Content Type",
"name": "content_type",
"value": "article"
},
{
"label": "Copyright",
"name": "copyright",
"value": "© 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences."
}
],
"author": [
{
"affiliation": [],
"family": "Gao",
"given": "Yumeng",
"sequence": "first"
},
{
"affiliation": [],
"family": "Zhang",
"given": "Jun",
"sequence": "additional"
}
],
"container-title": "Acta Pharmaceutica Sinica B",
"container-title-short": "Acta Pharmaceutica Sinica B",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"elsevier.com",
"sciencedirect.com"
]
},
"created": {
"date-parts": [
[
2025,
7,
5
]
],
"date-time": "2025-07-05T03:02:56Z",
"timestamp": 1751684576000
},
"deposited": {
"date-parts": [
[
2025,
9,
23
]
],
"date-time": "2025-09-23T05:34:04Z",
"timestamp": 1758605644000
},
"funder": [
{
"DOI": "10.13039/501100004826",
"award": [
"M23006"
],
"doi-asserted-by": "publisher",
"id": [
{
"asserted-by": "publisher",
"id": "10.13039/501100004826",
"id-type": "DOI"
}
],
"name": "Beijing Natural Science Foundation"
}
],
"indexed": {
"date-parts": [
[
2025,
9,
24
]
],
"date-time": "2025-09-24T00:06:56Z",
"timestamp": 1758672416021,
"version": "3.44.0"
},
"is-referenced-by-count": 0,
"issue": "9",
"issued": {
"date-parts": [
[
2025,
9
]
]
},
"journal-issue": {
"issue": "9",
"published-print": {
"date-parts": [
[
2025,
9
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://www.elsevier.com/tdm/userlicense/1.0/",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2025,
9,
1
]
],
"date-time": "2025-09-01T00:00:00Z",
"timestamp": 1756684800000
}
},
{
"URL": "https://www.elsevier.com/legal/tdmrep-license",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2025,
9,
1
]
],
"date-time": "2025-09-01T00:00:00Z",
"timestamp": 1756684800000
}
},
{
"URL": "http://creativecommons.org/licenses/by-nc-nd/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2025,
7,
1
]
],
"date-time": "2025-07-01T00:00:00Z",
"timestamp": 1751328000000
}
}
],
"link": [
{
"URL": "https://api.elsevier.com/content/article/PII:S2211383525004563?httpAccept=text/xml",
"content-type": "text/xml",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://api.elsevier.com/content/article/PII:S2211383525004563?httpAccept=text/plain",
"content-type": "text/plain",
"content-version": "vor",
"intended-application": "text-mining"
}
],
"member": "78",
"original-title": [],
"page": "4497-4510",
"prefix": "10.1016",
"published": {
"date-parts": [
[
2025,
9
]
]
},
"published-print": {
"date-parts": [
[
2025,
9
]
]
},
"publisher": "Elsevier BV",
"reference": [
{
"DOI": "10.1038/s41586-020-2008-3",
"article-title": "A new coronavirus associated with human respiratory disease in China",
"author": "Wu",
"doi-asserted-by": "crossref",
"first-page": "265",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib1",
"volume": "579",
"year": "2020"
},
{
"DOI": "10.1038/s41579-021-00630-8",
"article-title": "Structural biology of SARS-CoV-2 and implications for therapeutic development",
"author": "Yang",
"doi-asserted-by": "crossref",
"first-page": "685",
"journal-title": "Nat Rev Microbiol",
"key": "10.1016/j.apsb.2025.07.001_bib2",
"volume": "19",
"year": "2021"
},
{
"DOI": "10.3389/fimmu.2021.708264",
"article-title": "SARS-CoV-2 accessory proteins in viral pathogenesis: knowns and unknowns",
"author": "Redondo",
"doi-asserted-by": "crossref",
"journal-title": "Front Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib3",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1016/j.cell.2020.02.052",
"article-title": "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor",
"author": "Hoffmann",
"doi-asserted-by": "crossref",
"first-page": "271",
"journal-title": "Cell",
"key": "10.1016/j.apsb.2025.07.001_bib4",
"volume": "181",
"year": "2020"
},
{
"article-title": "Distinctive roles of furin and TMPRSS2 in SARS-CoV-2 infectivity",
"author": "Essalmani",
"journal-title": "J Virol",
"key": "10.1016/j.apsb.2025.07.001_bib5",
"volume": "96",
"year": "2022"
},
{
"DOI": "10.1038/s41392-020-00426-x",
"article-title": "CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells",
"author": "Wang",
"doi-asserted-by": "crossref",
"first-page": "283",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib6",
"volume": "5",
"year": "2020"
},
{
"DOI": "10.1126/science.abd2985",
"article-title": "Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity",
"author": "Cantuti-Castelvetri",
"doi-asserted-by": "crossref",
"first-page": "856",
"journal-title": "Science",
"key": "10.1016/j.apsb.2025.07.001_bib7",
"volume": "370",
"year": "2020"
},
{
"DOI": "10.1016/j.cell.2020.09.033",
"article-title": "SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2",
"author": "Clausen",
"doi-asserted-by": "crossref",
"first-page": "1043",
"journal-title": "Cell",
"key": "10.1016/j.apsb.2025.07.001_bib8",
"volume": "183",
"year": "2020"
},
{
"DOI": "10.1146/annurev-immunol-042617-053309",
"article-title": "RIG-I and other RNA sensors in antiviral immunity",
"author": "Chow",
"doi-asserted-by": "crossref",
"first-page": "667",
"journal-title": "Annu Rev Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib9",
"volume": "36",
"year": "2018"
},
{
"DOI": "10.15252/embj.2021107826",
"article-title": "SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation",
"author": "Thorne",
"doi-asserted-by": "crossref",
"journal-title": "EMBO J",
"key": "10.1016/j.apsb.2025.07.001_bib10",
"volume": "40",
"year": "2021"
},
{
"DOI": "10.1016/j.celrep.2020.108628",
"article-title": "MDA5 governs the innate immune response to SARS-CoV-2 in lung epithelial cells",
"author": "Yin",
"doi-asserted-by": "crossref",
"journal-title": "Cell Rep",
"key": "10.1016/j.apsb.2025.07.001_bib11",
"volume": "34",
"year": "2021"
},
{
"article-title": "Differential roles of RIG-I like receptors in SARS-CoV-2 infection",
"author": "Yang",
"first-page": "49",
"journal-title": "Mil Med Res",
"key": "10.1016/j.apsb.2025.07.001_bib12",
"volume": "8",
"year": "2021"
},
{
"DOI": "10.1038/s41577-020-0288-3",
"article-title": "RIG-I-like receptors: their regulation and roles in RNA sensing",
"author": "Rehwinkel",
"doi-asserted-by": "crossref",
"first-page": "537",
"journal-title": "Nat Rev Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib13",
"volume": "20",
"year": "2020"
},
{
"DOI": "10.1038/s41590-021-00942-0",
"article-title": "RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells",
"author": "Yamada",
"doi-asserted-by": "crossref",
"first-page": "820",
"journal-title": "Nat Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib14",
"volume": "22",
"year": "2021"
},
{
"DOI": "10.1038/s41392-021-00800-3",
"article-title": "Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection",
"author": "Zhou",
"doi-asserted-by": "crossref",
"first-page": "382",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib15",
"volume": "6",
"year": "2021"
},
{
"DOI": "10.1007/s10495-024-02025-5",
"article-title": "Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release",
"author": "Shteinfer-Kuzmine",
"doi-asserted-by": "crossref",
"first-page": "2025",
"journal-title": "Apoptosis",
"key": "10.1016/j.apsb.2025.07.001_bib16",
"volume": "29",
"year": "2024"
},
{
"DOI": "10.1038/s41467-021-25015-6",
"article-title": "SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation",
"author": "Pan",
"doi-asserted-by": "crossref",
"first-page": "4664",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib17",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1038/s41392-023-01368-w",
"article-title": "SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy",
"author": "Liang",
"doi-asserted-by": "crossref",
"first-page": "108",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib18",
"volume": "8",
"year": "2023"
},
{
"DOI": "10.1038/s41586-022-04702-4",
"article-title": "FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation",
"author": "Junqueira",
"doi-asserted-by": "crossref",
"first-page": "576",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib19",
"volume": "606",
"year": "2022"
},
{
"DOI": "10.3390/v14050999",
"article-title": "SARS-CoV-2 envelope (E) protein binds and activates TLR2 pathway: a novel molecular target for COVID-19 interventions",
"author": "Planès",
"doi-asserted-by": "crossref",
"first-page": "999",
"journal-title": "Viruses",
"key": "10.1016/j.apsb.2025.07.001_bib20",
"volume": "14",
"year": "2022"
},
{
"DOI": "10.3390/microorganisms9091820",
"article-title": "TLR3 and TLR7 RNA sensor activation during SARS-CoV-2 infection",
"author": "Bortolotti",
"doi-asserted-by": "crossref",
"first-page": "1820",
"journal-title": "Microorganisms",
"key": "10.1016/j.apsb.2025.07.001_bib21",
"volume": "9",
"year": "2021"
},
{
"DOI": "10.1038/s41423-020-00571-x",
"article-title": "SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response",
"author": "Fu",
"doi-asserted-by": "crossref",
"first-page": "613",
"journal-title": "Cell Mol Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib22",
"volume": "18",
"year": "2021"
},
{
"DOI": "10.1016/j.celrep.2021.108761",
"article-title": "SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO",
"author": "Wu",
"doi-asserted-by": "crossref",
"journal-title": "Cell Rep",
"key": "10.1016/j.apsb.2025.07.001_bib23",
"volume": "34",
"year": "2021"
},
{
"DOI": "10.1016/j.celrep.2020.108234",
"article-title": "Evasion of type I interferon by SARS-CoV-2",
"author": "Xia",
"doi-asserted-by": "crossref",
"journal-title": "Cell Rep",
"key": "10.1016/j.apsb.2025.07.001_bib24",
"volume": "33",
"year": "2020"
},
{
"DOI": "10.1080/22221751.2020.1780953",
"article-title": "SARS-CoV-2 nsp 13, nsp14, nsp15 and orf6 function as potent interferon antagonists",
"author": "Yuen",
"doi-asserted-by": "crossref",
"first-page": "1418",
"journal-title": "Emerg Microb Infect",
"key": "10.1016/j.apsb.2025.07.001_bib25",
"volume": "9",
"year": "2020"
},
{
"DOI": "10.1016/j.virusres.2020.198074",
"article-title": "The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway",
"author": "Li",
"doi-asserted-by": "crossref",
"journal-title": "Virus Res",
"key": "10.1016/j.apsb.2025.07.001_bib26",
"volume": "286",
"year": "2020"
},
{
"DOI": "10.1038/s41467-020-17665-9",
"article-title": "Activation and evasion of type I interferon responses by SARS-CoV-2",
"author": "Lei",
"doi-asserted-by": "crossref",
"first-page": "3810",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib27",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.1073/pnas.2016650117",
"article-title": "SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling",
"author": "Miorin",
"doi-asserted-by": "crossref",
"first-page": "28344",
"journal-title": "Proc Natl Acad Sci U S A",
"key": "10.1016/j.apsb.2025.07.001_bib28",
"volume": "117",
"year": "2020"
},
{
"DOI": "10.1002/ptr.7772",
"article-title": "Multi-target approach against SARS-CoV-2 by stone apple molecules: a master key to drug design",
"author": "Singh",
"doi-asserted-by": "crossref",
"first-page": "7",
"journal-title": "Phytother Res",
"key": "10.1016/j.apsb.2025.07.001_bib29",
"volume": "38",
"year": "2024"
},
{
"DOI": "10.1016/j.compbiomed.2021.104965",
"article-title": "Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: an in-silico approach",
"author": "Singh",
"doi-asserted-by": "crossref",
"journal-title": "Comput Biol Med",
"key": "10.1016/j.apsb.2025.07.001_bib30",
"volume": "139",
"year": "2021"
},
{
"DOI": "10.1080/07391102.2020.1766572",
"article-title": "Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors",
"author": "Bhardwaj",
"doi-asserted-by": "crossref",
"first-page": "3449",
"journal-title": "J Biomol Struct Dyn",
"key": "10.1016/j.apsb.2025.07.001_bib31",
"volume": "39",
"year": "2021"
},
{
"DOI": "10.1021/acs.jmedchem.4c02561",
"article-title": "Discovery of nirmatrelvir (PF-07321332): a potent, orally active inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) main protease",
"author": "Tuttle",
"doi-asserted-by": "crossref",
"first-page": "7003",
"journal-title": "J Med Chem",
"key": "10.1016/j.apsb.2025.07.001_bib32",
"volume": "68",
"year": "2025"
},
{
"DOI": "10.1126/science.abb3405",
"article-title": "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors",
"author": "Zhang",
"doi-asserted-by": "crossref",
"first-page": "409",
"journal-title": "Science",
"key": "10.1016/j.apsb.2025.07.001_bib33",
"volume": "368",
"year": "2020"
},
{
"DOI": "10.1038/s41586-020-2223-y",
"article-title": "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors",
"author": "Jin",
"doi-asserted-by": "crossref",
"first-page": "289",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib34",
"volume": "582",
"year": "2020"
},
{
"DOI": "10.1002/med.21783",
"article-title": "What coronavirus 3C-like protease tells us: from structure, substrate selectivity, to inhibitor design",
"author": "Xiong",
"doi-asserted-by": "crossref",
"first-page": "1965",
"journal-title": "Med Res Rev",
"key": "10.1016/j.apsb.2025.07.001_bib35",
"volume": "41",
"year": "2021"
},
{
"DOI": "10.1038/s41467-020-16954-7",
"article-title": "Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography",
"author": "Kneller",
"doi-asserted-by": "crossref",
"first-page": "3202",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib36",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.1038/s41467-020-19662-4",
"article-title": "Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site",
"author": "Lee",
"doi-asserted-by": "crossref",
"first-page": "5877",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib37",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.1038/s41467-022-32854-4",
"article-title": "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation",
"author": "Lee",
"doi-asserted-by": "crossref",
"first-page": "5196",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib38",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.3390/ijms21249523",
"article-title": "Identification of host cellular protein substrates of SARS-COV-2 main protease",
"author": "Miczi",
"doi-asserted-by": "crossref",
"first-page": "9523",
"journal-title": "IJMS",
"key": "10.1016/j.apsb.2025.07.001_bib39",
"volume": "21",
"year": "2020"
},
{
"DOI": "10.1186/s12863-022-01044-y",
"article-title": "Predicted coronavirus Nsp5 protease cleavage sites in the human proteome",
"author": "Scott",
"doi-asserted-by": "crossref",
"first-page": "25",
"journal-title": "BMC Genom Data",
"key": "10.1016/j.apsb.2025.07.001_bib40",
"volume": "23",
"year": "2022"
},
{
"DOI": "10.1002/pmic.202000246",
"article-title": "N-Terminomics for the identification of in vitro substrates and cleavage site specificity of the SARS-CoV-2 main protease",
"author": "Koudelka",
"doi-asserted-by": "crossref",
"journal-title": "Proteomics",
"key": "10.1016/j.apsb.2025.07.001_bib41",
"volume": "21",
"year": "2021"
},
{
"DOI": "10.1128/jvi.00037-22",
"article-title": "SARS-CoV-2 nsp5 exhibits stronger catalytic activity and interferon antagonism than its SARS-CoV ortholog",
"author": "Chen",
"doi-asserted-by": "crossref",
"journal-title": "J Virol",
"key": "10.1016/j.apsb.2025.07.001_bib42",
"volume": "96",
"year": "2022"
},
{
"DOI": "10.5483/BMBRep.2023-0153",
"article-title": "The N-terminal peptide of the main protease of SARS-CoV-2, targeting dimer interface, inhibits its proteolytic activity",
"author": "Song",
"doi-asserted-by": "crossref",
"first-page": "606",
"journal-title": "BMB Rep",
"key": "10.1016/j.apsb.2025.07.001_bib43",
"volume": "56",
"year": "2023"
},
{
"DOI": "10.1038/s41392-023-01418-3",
"article-title": "The main protease of SARS-CoV-2 downregulates innate immunity via a translational repression",
"author": "Liang",
"doi-asserted-by": "crossref",
"first-page": "162",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib44",
"volume": "8",
"year": "2023"
},
{
"DOI": "10.1128/mBio.02335-21",
"article-title": "SARS-CoV-2 Nsp5 demonstrates two distinct mechanisms targeting RIG-I and MAVS to evade the innate immune response",
"author": "Liu",
"doi-asserted-by": "crossref",
"journal-title": "mBio",
"key": "10.1016/j.apsb.2025.07.001_bib45",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1038/s41392-022-00878-3",
"article-title": "SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules",
"author": "Zheng",
"doi-asserted-by": "crossref",
"first-page": "22",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib46",
"volume": "7",
"year": "2022"
},
{
"DOI": "10.1038/s41392-020-00332-2",
"article-title": "Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling",
"author": "Wu",
"doi-asserted-by": "crossref",
"first-page": "221",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib47",
"volume": "5",
"year": "2020"
},
{
"article-title": "SARS-CoV-2 Nsp5 activates NF-κB pathway by upregulating SUMOylation of MAVS",
"author": "Li",
"journal-title": "Front Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib48",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1016/j.jbc.2023.105388",
"article-title": "E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro",
"author": "Lear",
"doi-asserted-by": "crossref",
"journal-title": "J Biol Chem",
"key": "10.1016/j.apsb.2025.07.001_bib49",
"volume": "299",
"year": "2023"
},
{
"DOI": "10.1021/acsinfecdis.3c00418",
"article-title": "Ubiquitin ligase parkin regulates the stability of SARS-CoV-2 main protease and suppresses viral replication",
"author": "Zhou",
"doi-asserted-by": "crossref",
"first-page": "879",
"journal-title": "ACS Infect Dis",
"key": "10.1016/j.apsb.2025.07.001_bib50",
"volume": "10",
"year": "2024"
},
{
"DOI": "10.2217/fvl-2020-0050",
"article-title": "Comparison of the COVID-2019 (SARS-CoV-2) pathogenesis with SARS-CoV and MERS-CoV infections",
"author": "Fani",
"doi-asserted-by": "crossref",
"first-page": "317",
"journal-title": "Future Virol",
"key": "10.1016/j.apsb.2025.07.001_bib51",
"volume": "15",
"year": "2020"
},
{
"DOI": "10.1007/s00018-024-05458-y",
"article-title": "MERS-CoV-nsp5 expression in human epithelial BEAS 2b cells attenuates type I interferon production by inhibiting IRF3 nuclear translocation",
"author": "Zhang",
"doi-asserted-by": "crossref",
"first-page": "433",
"journal-title": "Cell Mol Life Sci",
"key": "10.1016/j.apsb.2025.07.001_bib52",
"volume": "81",
"year": "2024"
},
{
"DOI": "10.3390/ijms26031197",
"article-title": "HCoV-229E Mpro suppresses RLR-mediated innate immune signalling through cleavage of NEMO and through other mechanisms",
"author": "Martiáñez-Vendrell",
"doi-asserted-by": "crossref",
"first-page": "1197",
"journal-title": "Int J Mol Sci",
"key": "10.1016/j.apsb.2025.07.001_bib53",
"volume": "26",
"year": "2025"
},
{
"DOI": "10.1016/j.ijbiomac.2022.04.077",
"article-title": "Expression, purification, and biophysical characterization of recombinant MERS-CoV main (Mpro) protease",
"author": "Almutairi",
"doi-asserted-by": "crossref",
"first-page": "984",
"journal-title": "Int J Biol Macromol",
"key": "10.1016/j.apsb.2025.07.001_bib54",
"volume": "209",
"year": "2022"
},
{
"DOI": "10.1016/j.virusres.2015.05.018",
"article-title": "Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus",
"author": "Wu",
"doi-asserted-by": "crossref",
"first-page": "56",
"journal-title": "Virus Res",
"key": "10.1016/j.apsb.2025.07.001_bib55",
"volume": "208",
"year": "2015"
},
{
"DOI": "10.1126/scisignal.ade1985",
"article-title": "The substrate selectivity of papain-like proteases from human-infecting coronaviruses correlates with innate immune suppression",
"author": "Xiong",
"doi-asserted-by": "crossref",
"journal-title": "Sci Signal",
"key": "10.1016/j.apsb.2025.07.001_bib56",
"volume": "16",
"year": "2023"
},
{
"DOI": "10.1038/s41586-020-2601-5",
"article-title": "Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity",
"author": "Shin",
"doi-asserted-by": "crossref",
"first-page": "657",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib57",
"volume": "587",
"year": "2020"
},
{
"DOI": "10.1074/jbc.RA118.005868",
"article-title": "The stress granule protein G3BP1 binds viral dsRNA and RIG-I to enhance interferon-β response",
"author": "Kim",
"doi-asserted-by": "crossref",
"first-page": "6430",
"journal-title": "J Biol Chem",
"key": "10.1016/j.apsb.2025.07.001_bib58",
"volume": "294",
"year": "2019"
},
{
"DOI": "10.1016/j.chom.2019.02.013",
"article-title": "NLRP12 regulates anti-viral RIG-I activation via interaction with TRIM25",
"author": "Chen",
"doi-asserted-by": "crossref",
"first-page": "602",
"journal-title": "Cell Host Microbe",
"key": "10.1016/j.apsb.2025.07.001_bib59",
"volume": "25",
"year": "2019"
},
{
"DOI": "10.1080/22221751.2020.1870414",
"article-title": "SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species",
"author": "Moustaqil",
"doi-asserted-by": "crossref",
"first-page": "178",
"journal-title": "Emerg Microb Infect",
"key": "10.1016/j.apsb.2025.07.001_bib60",
"volume": "10",
"year": "2021"
},
{
"DOI": "10.1038/s41392-021-00515-5",
"article-title": "Unique and complementary suppression of cGAS–STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins",
"author": "Rui",
"doi-asserted-by": "crossref",
"first-page": "123",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib61",
"volume": "6",
"year": "2021"
},
{
"DOI": "10.7150/ijbs.59943",
"article-title": "SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3",
"author": "Fung",
"doi-asserted-by": "crossref",
"first-page": "1547",
"journal-title": "Int J Biol Sci",
"key": "10.1016/j.apsb.2025.07.001_bib62",
"volume": "17",
"year": "2021"
},
{
"DOI": "10.1016/j.cyto.2021.155697",
"article-title": "SARS-CoV-2 3C-like protease antagonizes interferon-beta production by facilitating the degradation of IRF3",
"author": "Zhang",
"doi-asserted-by": "crossref",
"journal-title": "Cytokine",
"key": "10.1016/j.apsb.2025.07.001_bib63",
"volume": "148",
"year": "2021"
},
{
"DOI": "10.1128/spectrum.02322-22",
"article-title": "Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 is not required for NSP5-mediated inhibition of type I interferon signaling pathway",
"author": "Naik",
"doi-asserted-by": "crossref",
"journal-title": "Microbiol Spectr",
"key": "10.1016/j.apsb.2025.07.001_bib64",
"volume": "10",
"year": "2022"
},
{
"DOI": "10.1038/s41392-023-01630-1",
"article-title": "Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "374",
"journal-title": "Signal Transduct Targeted Ther",
"key": "10.1016/j.apsb.2025.07.001_bib65",
"volume": "8",
"year": "2023"
},
{
"DOI": "10.1016/j.jbc.2023.102990",
"article-title": "The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes",
"author": "Song",
"doi-asserted-by": "crossref",
"journal-title": "J Biol Chem",
"key": "10.1016/j.apsb.2025.07.001_bib66",
"volume": "299",
"year": "2023"
},
{
"DOI": "10.1371/journal.ppat.1011702",
"article-title": "Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3",
"author": "Wu",
"doi-asserted-by": "crossref",
"journal-title": "PLoS Pathog",
"key": "10.1016/j.apsb.2025.07.001_bib67",
"volume": "19",
"year": "2023"
},
{
"DOI": "10.1073/pnas.2107108118",
"article-title": "Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1",
"author": "Zhang",
"doi-asserted-by": "crossref",
"journal-title": "Proc Natl Acad Sci U S A",
"key": "10.1016/j.apsb.2025.07.001_bib68",
"volume": "118",
"year": "2021"
},
{
"DOI": "10.1128/jvi.01909-23",
"article-title": "SARS-CoV-2 and oncolytic EV-D68-encoded proteases differentially regulate pyroptosis",
"author": "Shen",
"doi-asserted-by": "crossref",
"first-page": "e0190923",
"journal-title": "J Virol",
"key": "10.1016/j.apsb.2025.07.001_bib69",
"volume": "98",
"year": "2024"
},
{
"DOI": "10.1128/mbio.02739-21",
"article-title": "Coronaviruses Nsp5 antagonizes porcine Gasdermin D-mediated pyroptosis by cleaving pore-forming p30 fragment",
"author": "Shi",
"doi-asserted-by": "crossref",
"journal-title": "mBio",
"key": "10.1016/j.apsb.2025.07.001_bib70",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.1016/j.molcel.2022.04.033",
"article-title": "Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells",
"author": "Planès",
"doi-asserted-by": "crossref",
"first-page": "2385",
"journal-title": "Mol Cell",
"key": "10.1016/j.apsb.2025.07.001_bib71",
"volume": "82",
"year": "2022"
},
{
"DOI": "10.1016/j.celrep.2024.115080",
"article-title": "SARS-CoV-2 3CLpro (main protease) regulates caspase activation of gasdermin-D/E pores leading to secretion and extracellular activity of 3CLpro",
"author": "Grin",
"doi-asserted-by": "crossref",
"journal-title": "Cell Rep",
"key": "10.1016/j.apsb.2025.07.001_bib72",
"volume": "43",
"year": "2024"
},
{
"DOI": "10.3390/cells13191614",
"article-title": "A gain-of-function cleavage of TonEBP by coronavirus NSP5 to suppress IFN-β expression",
"author": "Park",
"doi-asserted-by": "crossref",
"first-page": "1614",
"journal-title": "Cells",
"key": "10.1016/j.apsb.2025.07.001_bib73",
"volume": "13",
"year": "2024"
},
{
"DOI": "10.1093/jmcb/mjad024",
"article-title": "SARS-CoV-2 main protease Nsp5 cleaves and inactivates human tRNA methyltransferase TRMT1",
"author": "Lu",
"doi-asserted-by": "crossref",
"journal-title": "J Mol Cell Biol",
"key": "10.1016/j.apsb.2025.07.001_bib74",
"volume": "15",
"year": "2023"
},
{
"DOI": "10.1186/s43556-022-00083-2",
"article-title": "Cleavage of the selective autophagy receptor SQSTM1/p62 by the SARS-CoV-2 main protease NSP5 prevents the autophagic degradation of viral membrane proteins",
"author": "Zhang",
"doi-asserted-by": "crossref",
"first-page": "17",
"journal-title": "Mol Biomed",
"key": "10.1016/j.apsb.2025.07.001_bib75",
"volume": "3",
"year": "2022"
},
{
"DOI": "10.3390/cells12091282",
"article-title": "Autophagy receptor p62 regulates SARS-CoV-2-induced inflammation in COVID-19",
"author": "Paunovic",
"doi-asserted-by": "crossref",
"first-page": "1282",
"journal-title": "Cells",
"key": "10.1016/j.apsb.2025.07.001_bib76",
"volume": "12",
"year": "2023"
},
{
"article-title": "SARS-CoV-2 main protease cleaves MAGED2 to antagonize host antiviral defense",
"author": "Ju",
"journal-title": "mBio",
"key": "10.1016/j.apsb.2025.07.001_bib77",
"volume": "14",
"year": "2023"
},
{
"DOI": "10.3390/v14051039",
"article-title": "Signaling pathway reporter screen with SARS-CoV-2 proteins identifies nsp5 as a repressor of p53 activity",
"author": "Kumar",
"doi-asserted-by": "crossref",
"first-page": "1039",
"journal-title": "Viruses",
"key": "10.1016/j.apsb.2025.07.001_bib78",
"volume": "14",
"year": "2022"
},
{
"DOI": "10.1128/mbio.03359-22",
"article-title": "SARS-CoV-2 SUD2 and Nsp5 conspire to boost apoptosis of respiratory epithelial cells via an augmented interaction with the G-quadruplex of BclII",
"author": "Li",
"doi-asserted-by": "crossref",
"journal-title": "mBio",
"key": "10.1016/j.apsb.2025.07.001_bib79",
"volume": "14",
"year": "2023"
},
{
"DOI": "10.1016/j.molcel.2018.07.034",
"article-title": "Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signaling after nuclear DNA damage",
"author": "Dunphy",
"doi-asserted-by": "crossref",
"first-page": "745",
"journal-title": "Mol Cell",
"key": "10.1016/j.apsb.2025.07.001_bib80",
"volume": "71",
"year": "2018"
},
{
"DOI": "10.1038/s41580-020-0244-x",
"article-title": "Molecular mechanisms and cellular functions of cGAS–STING signalling",
"author": "Hopfner",
"doi-asserted-by": "crossref",
"first-page": "501",
"journal-title": "Nat Rev Mol Cell Biol",
"key": "10.1016/j.apsb.2025.07.001_bib81",
"volume": "21",
"year": "2020"
},
{
"DOI": "10.1146/annurev-immunol-032713-120231",
"article-title": "Interferon-stimulated genes: a complex web of host defenses",
"author": "Schneider",
"doi-asserted-by": "crossref",
"first-page": "513",
"journal-title": "Annu Rev Immunol",
"key": "10.1016/j.apsb.2025.07.001_bib82",
"volume": "32",
"year": "2014"
},
{
"article-title": "SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon",
"author": "Shemesh",
"journal-title": "PLoS Pathog",
"key": "10.1016/j.apsb.2025.07.001_bib83",
"volume": "17",
"year": "2021"
},
{
"DOI": "10.1016/j.mam.2020.100887",
"article-title": "NLRP12 in innate immunity and inflammation",
"author": "Tuladhar",
"doi-asserted-by": "crossref",
"journal-title": "Mol Aspects Med",
"key": "10.1016/j.apsb.2025.07.001_bib84",
"volume": "76",
"year": "2020"
},
{
"DOI": "10.1016/j.immuni.2006.08.009",
"article-title": "Type I inteferon gene induction by the interferon regulatory factor family of transcription factors",
"author": "Honda",
"doi-asserted-by": "crossref",
"first-page": "349",
"journal-title": "Immunity",
"key": "10.1016/j.apsb.2025.07.001_bib85",
"volume": "25",
"year": "2006"
},
{
"DOI": "10.1126/science.1184004",
"article-title": "How the non-inflammasome NLRs function in the innate immune system",
"author": "Ting",
"doi-asserted-by": "crossref",
"first-page": "286",
"journal-title": "Science",
"key": "10.1016/j.apsb.2025.07.001_bib86",
"volume": "327",
"year": "2010"
},
{
"DOI": "10.1038/nature15514",
"article-title": "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death",
"author": "Shi",
"doi-asserted-by": "crossref",
"first-page": "660",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib87",
"volume": "526",
"year": "2015"
},
{
"DOI": "10.1128/MCB.00214-17",
"article-title": "TRMT1-catalyzed tRNA modifications are required for redox homeostasis to ensure proper cellular proliferation and oxidative stress survival",
"author": "Dewe",
"doi-asserted-by": "crossref",
"journal-title": "Mol Cell Biol",
"key": "10.1016/j.apsb.2025.07.001_bib88",
"volume": "37",
"year": "2017"
},
{
"DOI": "10.3390/v2010298",
"article-title": "Dual role of p53 in innate antiviral immunity",
"author": "Rivas",
"doi-asserted-by": "crossref",
"first-page": "298",
"journal-title": "Viruses",
"key": "10.1016/j.apsb.2025.07.001_bib89",
"volume": "2",
"year": "2010"
},
{
"DOI": "10.1093/nar/gkab571",
"article-title": "SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction",
"author": "Lavigne",
"doi-asserted-by": "crossref",
"first-page": "7695",
"journal-title": "Nucleic Acids Res",
"key": "10.1016/j.apsb.2025.07.001_bib90",
"volume": "49",
"year": "2021"
},
{
"DOI": "10.1371/journal.ppat.1009412",
"article-title": "The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation",
"author": "Meyers",
"doi-asserted-by": "crossref",
"journal-title": "PLoS Pathog",
"key": "10.1016/j.apsb.2025.07.001_bib91",
"volume": "17",
"year": "2021"
},
{
"DOI": "10.1126/science.abl4784",
"article-title": "An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19",
"author": "Owen",
"doi-asserted-by": "crossref",
"first-page": "1586",
"journal-title": "Science",
"key": "10.1016/j.apsb.2025.07.001_bib92",
"volume": "374",
"year": "2021"
},
{
"DOI": "10.1056/NEJMoa2118542",
"article-title": "Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19",
"author": "Hammond",
"doi-asserted-by": "crossref",
"first-page": "1397",
"journal-title": "N Engl J Med",
"key": "10.1016/j.apsb.2025.07.001_bib93",
"volume": "386",
"year": "2022"
},
{
"DOI": "10.1007/s40265-022-01692-5",
"article-title": "Nirmatrelvir plus ritonavir: first approval",
"author": "Lamb",
"doi-asserted-by": "crossref",
"first-page": "585",
"journal-title": "Drugs",
"key": "10.1016/j.apsb.2025.07.001_bib94",
"volume": "82",
"year": "2022"
},
{
"DOI": "10.1007/s40261-023-01309-z",
"article-title": "A phase 1 study of ensitrelvir fumaric acid tablets evaluating the safety, pharmacokinetics and food effect in healthy adult populations",
"author": "Shimizu",
"doi-asserted-by": "crossref",
"first-page": "785",
"journal-title": "Clin Drug Invest",
"key": "10.1016/j.apsb.2025.07.001_bib95",
"volume": "43",
"year": "2023"
},
{
"DOI": "10.1128/aac.00697-22",
"article-title": "A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part",
"author": "Mukae",
"doi-asserted-by": "crossref",
"journal-title": "Antimicrob Agents Chemother",
"key": "10.1016/j.apsb.2025.07.001_bib96",
"volume": "66",
"year": "2022"
},
{
"DOI": "10.1001/jamanetworkopen.2023.54991",
"article-title": "Efficacy and safety of 5-day oral ensitrelvir for patients with mild to moderate COVID-19",
"author": "Yotsuyanagi",
"doi-asserted-by": "crossref",
"journal-title": "JAMA Netw Open",
"key": "10.1016/j.apsb.2025.07.001_bib97",
"volume": "7",
"year": "2024"
},
{
"DOI": "10.1016/j.eclinm.2023.102189",
"article-title": "Antiviral efficacy of RAY1216 monotherapy and combination therapy with ritonavir in patients with COVID-19: a phase 2, single centre, randomised, double-blind, placebo-controlled trial",
"author": "Wang",
"doi-asserted-by": "crossref",
"journal-title": "eClinicalMedicine",
"key": "10.1016/j.apsb.2025.07.001_bib98",
"volume": "63",
"year": "2023"
},
{
"DOI": "10.1016/j.eclinm.2023.102359",
"article-title": "Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial",
"author": "Zhan",
"doi-asserted-by": "crossref",
"first-page": "102359",
"journal-title": "eClinicalMedicine",
"key": "10.1016/j.apsb.2025.07.001_bib99",
"volume": "67",
"year": "2023"
},
{
"DOI": "10.1016/j.ejps.2023.106598",
"article-title": "A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects",
"author": "Yang",
"doi-asserted-by": "crossref",
"journal-title": "Eur J Pharmaceut Sci",
"key": "10.1016/j.apsb.2025.07.001_bib100",
"volume": "191",
"year": "2023"
},
{
"DOI": "10.1056/NEJMoa2301425",
"article-title": "Oral simnotrelvir for adult patients with mild-to-moderate Covid-19",
"author": "Cao",
"doi-asserted-by": "crossref",
"first-page": "230",
"journal-title": "N Engl J Med",
"key": "10.1016/j.apsb.2025.07.001_bib101",
"volume": "390",
"year": "2024"
},
{
"DOI": "10.1128/aac.01115-23",
"article-title": "Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171",
"author": "Zhang",
"doi-asserted-by": "crossref",
"journal-title": "Antimicrob Agents Chemother",
"key": "10.1016/j.apsb.2025.07.001_bib102",
"volume": "68",
"year": "2024"
},
{
"DOI": "10.1016/j.eclinm.2024.102582",
"article-title": "Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial",
"author": "Lu",
"doi-asserted-by": "crossref",
"journal-title": "eClinicalMedicine",
"key": "10.1016/j.apsb.2025.07.001_bib103",
"volume": "71",
"year": "2024"
},
{
"DOI": "10.1016/j.medj.2024.01.013",
"article-title": "Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19",
"author": "Mao",
"doi-asserted-by": "crossref",
"first-page": "169",
"journal-title": "Med",
"key": "10.1016/j.apsb.2025.07.001_bib104",
"volume": "5",
"year": "2024"
},
{
"DOI": "10.1056/EVIDoa2400026",
"article-title": "Olgotrelvir as a single-agent treatment of nonhospitalized patients with Covid-19",
"author": "Jiang",
"doi-asserted-by": "crossref",
"journal-title": "NEJM Evid",
"key": "10.1016/j.apsb.2025.07.001_bib105",
"volume": "3",
"year": "2024"
},
{
"DOI": "10.1001/jamanetworkopen.2024.39332",
"article-title": "Time to sustained recovery among outpatients with COVID-19 receiving montelukast vs placebo: the ACTIV-6 randomized clinical trial",
"author": "Rothman",
"doi-asserted-by": "crossref",
"journal-title": "JAMA Netw Open",
"key": "10.1016/j.apsb.2025.07.001_bib106",
"volume": "7",
"year": "2024"
},
{
"DOI": "10.1128/spectrum.02980-23",
"article-title": "SARS-CoV-2 viral dynamics in a placebo-controlled phase 2 study of patients infected with the SARS-CoV-2 Omicron variant and treated with pomotrelvir",
"author": "Borroto-Esoda",
"doi-asserted-by": "crossref",
"journal-title": "Microbiol Spectr",
"key": "10.1016/j.apsb.2025.07.001_bib107",
"volume": "12",
"year": "2024"
},
{
"DOI": "10.1093/cid/ciae529",
"article-title": "Virologic response and safety of ibuzatrelvir, a novel SARS-CoV-2 antiviral, in adults with COVID-19",
"author": "Mortezavi",
"doi-asserted-by": "crossref",
"first-page": "673",
"journal-title": "Clin Infect Dis",
"key": "10.1016/j.apsb.2025.07.001_bib108",
"volume": "80",
"year": "2025"
},
{
"DOI": "10.1007/s13238-021-00883-2",
"article-title": "Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332",
"author": "Zhao",
"doi-asserted-by": "crossref",
"first-page": "689",
"journal-title": "Protein Cell",
"key": "10.1016/j.apsb.2025.07.001_bib109",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.1016/S1473-3099(24)00353-0",
"article-title": "Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study",
"author": "Choi",
"doi-asserted-by": "crossref",
"first-page": "1213",
"journal-title": "Lancet Infect Dis",
"key": "10.1016/j.apsb.2025.07.001_bib110",
"volume": "24",
"year": "2024"
},
{
"DOI": "10.1016/j.jinf.2024.106190",
"article-title": "Early use of oral antiviral drugs and the risk of post COVID-19 syndrome: a systematic review and network meta-analysis",
"author": "Jiang",
"doi-asserted-by": "crossref",
"journal-title": "J Infect",
"key": "10.1016/j.apsb.2025.07.001_bib111",
"volume": "89",
"year": "2024"
},
{
"DOI": "10.1001/jama.2024.16432",
"article-title": "The latest research about paxlovid: effectiveness, access, and possible long COVID benefits",
"author": "Rubin",
"doi-asserted-by": "crossref",
"first-page": "1040",
"journal-title": "JAMA",
"key": "10.1016/j.apsb.2025.07.001_bib112",
"volume": "332",
"year": "2024"
},
{
"DOI": "10.1038/s42003-023-05071-y",
"article-title": "Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants",
"author": "Lin",
"doi-asserted-by": "crossref",
"first-page": "694",
"journal-title": "Commun Biol",
"key": "10.1016/j.apsb.2025.07.001_bib113",
"volume": "6",
"year": "2023"
},
{
"DOI": "10.1016/j.antiviral.2024.105859",
"article-title": "A combination of nirmatrelvir and ombitasvir boosts inhibition of SARS-CoV-2 replication",
"author": "Moon",
"doi-asserted-by": "crossref",
"journal-title": "Antiviral Res",
"key": "10.1016/j.apsb.2025.07.001_bib114",
"volume": "225",
"year": "2024"
},
{
"DOI": "10.3390/v16020168",
"article-title": "In vitro combinatorial activity of direct acting antivirals and monoclonal antibodies against the ancestral B.1 and BQ.1.1 SARS-CoV-2 viral variants",
"author": "Fiaschi",
"doi-asserted-by": "crossref",
"first-page": "168",
"journal-title": "Viruses",
"key": "10.1016/j.apsb.2025.07.001_bib115",
"volume": "16",
"year": "2024"
},
{
"DOI": "10.3390/v15071577",
"article-title": "Synergistic activity of remdesivir–nirmatrelvir combination on a SARS-CoV-2 in vitro model and a case report",
"author": "Gidari",
"doi-asserted-by": "crossref",
"first-page": "1577",
"journal-title": "Viruses",
"key": "10.1016/j.apsb.2025.07.001_bib116",
"volume": "15",
"year": "2023"
},
{
"DOI": "10.1093/jac/dkae482",
"article-title": "Efficacy and safety of antiviral therapies for the treatment of persistent COVID-19 in immunocompromised patients since the Omicron surge: a systematic review",
"author": "Hirsch",
"doi-asserted-by": "crossref",
"first-page": "633",
"journal-title": "J Antimicrob Chemother",
"key": "10.1016/j.apsb.2025.07.001_bib117",
"volume": "80",
"year": "2025"
},
{
"DOI": "10.1016/j.phymed.2023.155025",
"article-title": "Efficacy and safety of Huashi Baidu granule plus Nirmatrelvir-Ritonavir combination therapy in patients with high-risk factors infected with Omicron (B.1.1.529): a multi-arm single-center, open-label, randomized controlled trial",
"author": "Yu",
"doi-asserted-by": "crossref",
"journal-title": "Phytomedicine",
"key": "10.1016/j.apsb.2025.07.001_bib118",
"volume": "120",
"year": "2023"
},
{
"DOI": "10.1016/j.apsb.2023.06.001",
"article-title": "Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine",
"author": "Ye",
"doi-asserted-by": "crossref",
"first-page": "3598",
"journal-title": "Acta Pharm Sin B",
"key": "10.1016/j.apsb.2025.07.001_bib119",
"volume": "13",
"year": "2023"
},
{
"DOI": "10.1016/j.ebiom.2023.104950",
"article-title": "Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model",
"author": "Sasaki",
"doi-asserted-by": "crossref",
"journal-title": "EBioMedicine",
"key": "10.1016/j.apsb.2025.07.001_bib120",
"volume": "99",
"year": "2024"
},
{
"DOI": "10.1038/s41586-022-05514-2",
"article-title": "Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir",
"author": "Iketani",
"doi-asserted-by": "crossref",
"first-page": "558",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib121",
"volume": "613",
"year": "2023"
},
{
"DOI": "10.1038/s41586-023-06609-0",
"article-title": "Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir",
"author": "Duan",
"doi-asserted-by": "crossref",
"first-page": "376",
"journal-title": "Nature",
"key": "10.1016/j.apsb.2025.07.001_bib122",
"volume": "622",
"year": "2023"
},
{
"DOI": "10.1038/s41467-025-56651-x",
"article-title": "Distal protein–protein interactions contribute to nirmatrelvir resistance",
"author": "Lewandowski",
"doi-asserted-by": "crossref",
"first-page": "1266",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib123",
"volume": "16",
"year": "2025"
},
{
"DOI": "10.1038/s41467-023-40018-1",
"article-title": "In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir",
"author": "Kiso",
"doi-asserted-by": "crossref",
"first-page": "4231",
"journal-title": "Nat Commun",
"key": "10.1016/j.apsb.2025.07.001_bib124",
"volume": "14",
"year": "2023"
},
{
"DOI": "10.1016/j.ebiom.2023.104559",
"article-title": "Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance",
"author": "Ip",
"doi-asserted-by": "crossref",
"journal-title": "EBioMedicine",
"key": "10.1016/j.apsb.2025.07.001_bib125",
"volume": "91",
"year": "2023"
},
{
"DOI": "10.1002/smsc.202270012",
"article-title": "Oridonin inhibits SARS-CoV-2 by targeting its 3C-like protease",
"author": "Zhong",
"doi-asserted-by": "crossref",
"journal-title": "Small Sci",
"key": "10.1016/j.apsb.2025.07.001_bib126",
"volume": "2",
"year": "2022"
},
{
"DOI": "10.1016/j.virs.2023.04.008",
"article-title": "Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase",
"author": "Zhang",
"doi-asserted-by": "crossref",
"first-page": "470",
"journal-title": "Virol Sin",
"key": "10.1016/j.apsb.2025.07.001_bib127",
"volume": "38",
"year": "2023"
},
{
"article-title": "An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo",
"author": "Chu",
"journal-title": "Res Sq",
"key": "10.1016/j.apsb.2025.07.001_bib128",
"year": "2024"
},
{
"DOI": "10.1126/scitranslmed.adi0979",
"article-title": "An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations",
"author": "Westberg",
"doi-asserted-by": "crossref",
"journal-title": "Sci Transl Med",
"key": "10.1016/j.apsb.2025.07.001_bib129",
"volume": "16",
"year": "2024"
},
{
"DOI": "10.1016/j.antiviral.2024.106038",
"article-title": "Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity",
"author": "McGovern-Gooch",
"doi-asserted-by": "crossref",
"journal-title": "Antivir Res",
"key": "10.1016/j.apsb.2025.07.001_bib130",
"volume": "232",
"year": "2024"
},
{
"DOI": "10.1021/acs.jmedchem.4c01639",
"article-title": "De novo discovery of a noncovalent cell-penetrating bicyclic peptide inhibitor targeting SARS-CoV-2 main protease",
"author": "Tan",
"doi-asserted-by": "crossref",
"first-page": "20258",
"journal-title": "J Med Chem",
"key": "10.1016/j.apsb.2025.07.001_bib131",
"volume": "67",
"year": "2024"
},
{
"DOI": "10.1021/acs.jmedchem.4c02009",
"article-title": "Rational design of macrocyclic noncovalent inhibitors of SARS-CoV-2 Mpro from a DNA-encoded chemical library screening hit that demonstrate potent inhibition against pan-coronavirus homologues and nirmatrelvir-resistant variants",
"author": "Wang",
"doi-asserted-by": "crossref",
"first-page": "19623",
"journal-title": "J Med Chem",
"key": "10.1016/j.apsb.2025.07.001_bib132",
"volume": "67",
"year": "2024"
},
{
"DOI": "10.1021/acs.jcim.4c01206",
"article-title": "Molecular mechanism-driven discovery of novel small molecule inhibitors against drug-resistant SARS-CoV-2 Mpro variants",
"author": "Yang",
"doi-asserted-by": "crossref",
"first-page": "7998",
"journal-title": "J Chem Inf Model",
"key": "10.1016/j.apsb.2025.07.001_bib133",
"volume": "64",
"year": "2024"
},
{
"article-title": "Miniaturized modular click chemistry-enabled rapid discovery of unique SARS-CoV-2 Mpro inhibitors with robust potency and drug-like profile",
"author": "Yang",
"journal-title": "Adv Sci (Weinh)",
"key": "10.1016/j.apsb.2025.07.001_bib134",
"volume": "11",
"year": "2024"
},
{
"DOI": "10.1016/j.antiviral.2024.105920",
"article-title": "Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants",
"author": "Le",
"doi-asserted-by": "crossref",
"journal-title": "Antiviral Res",
"key": "10.1016/j.apsb.2025.07.001_bib135",
"volume": "227",
"year": "2024"
},
{
"DOI": "10.1021/acs.jnatprod.3c01071",
"article-title": "Metabolomic analysis and antiviral screening of a marine algae library yield jobosic acid (2,5-dimethyltetradecanoic acid) as a selective inhibitor of SARS-CoV-2",
"author": "Matos-Hernández",
"doi-asserted-by": "crossref",
"first-page": "1513",
"journal-title": "J Nat Prod",
"key": "10.1016/j.apsb.2025.07.001_bib136",
"volume": "87",
"year": "2024"
},
{
"DOI": "10.1016/j.antiviral.2024.105841",
"article-title": "Methyl rosmarinate is an allosteric inhibitor of SARS-CoV-2 3 CL protease as a potential candidate against SARS-cov-2 infection",
"author": "Li",
"doi-asserted-by": "crossref",
"journal-title": "Antiviral Res",
"key": "10.1016/j.apsb.2025.07.001_bib137",
"volume": "224",
"year": "2024"
},
{
"DOI": "10.3389/fmolb.2024.1451280",
"article-title": "A potential allosteric inhibitor of SARS-CoV-2 main protease (Mpro) identified through metastable state analysis",
"author": "Fatima",
"doi-asserted-by": "crossref",
"journal-title": "Front Mol Biosci",
"key": "10.1016/j.apsb.2025.07.001_bib138",
"volume": "11",
"year": "2024"
},
{
"DOI": "10.1021/jacs.3c12678",
"article-title": "A chemical strategy for the degradation of the main protease of SARS-CoV-2 in cells",
"author": "Sang",
"doi-asserted-by": "crossref",
"first-page": "27248",
"journal-title": "J Am Chem Soc",
"key": "10.1016/j.apsb.2025.07.001_bib139",
"volume": "145",
"year": "2023"
},
{
"DOI": "10.1021/acs.jmedchem.3c02416",
"article-title": "Discovery of first-in-class PROTAC degraders of SARS-CoV-2 main protease",
"author": "Alugubelli",
"doi-asserted-by": "crossref",
"first-page": "6495",
"journal-title": "J Med Chem",
"key": "10.1016/j.apsb.2025.07.001_bib140",
"volume": "67",
"year": "2024"
}
],
"reference-count": 140,
"references-count": 140,
"relation": {},
"resource": {
"primary": {
"URL": "https://linkinghub.elsevier.com/retrieve/pii/S2211383525004563"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications",
"type": "journal-article",
"update-policy": "https://doi.org/10.1016/elsevier_cm_policy",
"volume": "15"
}
