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All Studies   Meta Analysis    Recent:   

Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

Munafò et al., Research Square, doi:10.21203/rs.3.rs-1149846/v1
Dec 2021  
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Quercetin for COVID-19
24th treatment shown to reduce risk in July 2021
 
*, now with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,800+ studies for 98 treatments. c19early.org
In Vitro and In Silico study showing quercetin and luteolin inhibiting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
64 preclinical studies support the efficacy of quercetin for COVID-19:
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,4,5,17,19,20,25,33,34,36,37,55,56, MproB,2,4,6,8,10,12,13,15,18,19,25,29,31-33,37,38,40,56,57, RNA-dependent RNA polymeraseC,4,27, PLproD,32,40, ACE2E,17,18,23,32,36,56, TMPRSS2F,17, helicaseG,24,29, endoribonucleaseH,34, cathepsin LI,21, Wnt-3J,17, FZDK,17, LRP6L,17, ezrinM,35, ADRPN,33, NRP1O,36, EP300P,11, PTGS2Q,18, HSP90AA1R,11,18, matrix metalloproteinase 9S,26, IL-6T,16,30, IL-10U,16, VEGFAV,30, and RELAW,30 proteins. In Vitro studies demonstrate inhibition of the MproB,10,45,52 protein, and inhibition of spike-ACE2 interactionX,41. In Vitro studies demonstrate efficacy in Calu-3Y,44, A549Z,16, HEK293-ACE2+AA,51, Huh-7AB,20, Caco-2AC,43, Vero E6AD,14,37,43, mTECAE,46, and RAW264.7AF,46 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAG,48, db/db miceAH,46,54, BALB/c miceAI,53, and rats58. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice53 and inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages1.
Munafò et al., 28 Dec 2021, preprint, 6 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase
Federico Munafò, Elisa Donati, Nicoletta Brindani, Giuliano Ottonello, Andrea Armirotti, Marco De Vivo
doi:10.21203/rs.3.rs-1149846/v1
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as one of the most promising targets for pharmacological intervention against SARS-CoV-2. To this end, we experimentally tested luteolin and quercetin for their ability to inhibit the RdRp enzyme. These two compounds are ancestors of avonoid natural compounds known for a variety of basal pharmacological activities. Luteolin and quercetin returned a single-digit IC 50 of 4.6 µM and 6.9 µM, respectively. Then, through dynamic docking simulations, we identi ed possible binding modes of these compounds to a recently published cryo-EM structure of RdRp. Collectively, these data indicate that these two compounds are a valid starting point for further optimization and development of a new class of RdRp inhibitors to treat SARS-CoV-2 and potentially other viral infections.
Supporting Information. Supplementary gures reporting the: i) chromatography analysis of luteolin and quercetin (pages S2−S3), ii) chemical structures of luteolin and quercetin in different protonation states (page S4), iii) docking scores (page S5), iv) MD analysis (pages S6-S9). Supplementary Files This is a list of supplementary les associated with this preprint. Click to download.
References
Abian, Structural stability of SARS-CoV-2 3CLpro and identi cation of quercetin as an inhibitor by experimental screening, Int J Biol Macromol, doi:10.1016/j.ijbiomac.2020.07.235
Arencibia, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity, J Med Chem, doi:10.1021/acs.jmedchem.9b01760
Bayly, Cieplak, Cornell, Kollman, A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model, The Journal of Physical Chemistry, doi:10.1021/j100142a004
Bussi, Donadio, Parrinello, Canonical sampling through velocity rescaling, J Chem Phys, doi:10.1063/1.2408420
Carta, Quinoline tricyclic derivatives. Design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors, Bioorg Med Chem, doi:10.1016/j.bmc.2011.10.009
Casalino, AI-driven multiscale simulations illuminate mechanisms of SARS-CoV-2 spike dynamics, The International Journal of High Performance Computing Applications, doi:10.1177/10943420211006452
Chen, Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex, Cell, doi:10.1016/j.cell.2020.07.033
Chien, Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19, J Proteome Res, doi:10.1021/acs.jproteome.0c00392
Choudhry, Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), J Med Chem, doi:10.1021/acs.jmedchem.0c00626
De, Vivo, Cavalli, Recent advances in dynamic docking for drug discovery, WIREs Computational Molecular Science, doi:10.1002/wcms.1320
De, Vivo, Masetti, Bottegoni, Cavalli, Role of Molecular Dynamics and Related Methods in Drug Discovery, J Med Chem, doi:10.1021/acs.jmedchem.5b01684
Derosa, Ma Oli, D'angelo, Di Pierro, A role for quercetin in coronavirus disease 2019 (COVID-19), Phytother Res, doi:10.1002/ptr.6887
Deshmukh, Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease, Structure, doi:10.1016/j.str.2021.06.002
Friesner, Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J Med Chem, doi:10.1021/jm0306430
Genna, Donati, De Vivo, The Catalytic Mechanism of DNA and RNA Polymerases, ACS Catalysis, doi:10.1021/acscatal.8b03363
Geronimo, Vidossich, Donati, Vivo, Computational investigations of polymerase enzymes: Structure, function, inhibition, and biotechnology, WIREs Computational Molecular Science, doi:10.1002/wcms.1534
Ghahremanpour, Identi cation of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2, ACS Med Chem Lett, doi:10.1021/acsmedchemlett.0c00521
Goris, Repositioning microbial biotechnology against COVID-19: the case of microbial production of avonoids, Microb Biotechnol, doi:10.1111/1751-7915.13675
Halgren, Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening, J Med Chem, doi:10.1021/jm030644s
Hess, P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation, J Chem Theory Comput, doi:10.1021/ct700200b
Hillen, Structure of replicating SARS-CoV-2 polymerase, Nature, doi:10.1038/s41586-020-2368-8
Huang, Song, Huang, Sun, Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19
Jockusch, A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19, Antiviral Res, doi:10.1016/j.antiviral.2020.104857
Joung, Cheatham, Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations, J Phys Chem B, doi:10.1021/jp8001614
Khan, A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase, Int J Biol Macromol, doi:10.1016/j.ijbiomac.2021.03.112
Kokic, Mechanism of SARS-CoV-2 polymerase stalling by remdesivir, Nat Commun, doi:10.1038/s41467-020-20542-0
Lee, Investigation of the pharmacophore space of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) NTPase/helicase by dihydroxychromone derivatives, Bioorg Med Chem Lett, doi:10.1016/j.bmcl.2009.07.009
Li, De Clercq, Therapeutic options for the 2019 novel coronavirus (2019-nCoV), Nat Rev Drug Discov, doi:10.1038/d41573-020-00016-0
Liskova, Flavonoids against the SARS-CoV-2 induced in ammatory storm, Biomed Pharmacother, doi:10.1016/j.biopha.2021.111430
Maier, Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB, J Chem Theory Comput, doi:10.1021/acs.jctc.5b00255
Malone, Campbell, Molnupiravir: coding for catastrophe, Nat Struct Mol Biol, doi:10.1038/s41594-021-00657-8
Mishra, Rathore, RNA dependent RNA polymerase (RdRp) as a drug target for SARS-CoV2, J Biomol Struct Dyn, doi:10.1080/07391102.2021.1875886
Naydenova, Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2021946118
Newman, Cragg, Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019, J Nat Prod, doi:10.1021/acs.jnatprod.9b01285
Nguyen, Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris, Biotechnol Lett, doi:10.1007/s10529-011-0845-8
Ortega, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II alpha over beta, J Med Chem, doi:10.1021/acs.jmedchem.0c00774
Palermo, An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quanti ed by comparative analysis centered on the clinical candidate F14512, Chem Commun (Camb), doi:10.1039/c5cc05065k
Palermo, Favia, Convertino, De Vivo, The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition, ChemMedChem, doi:10.1002/cmdc.201500507
Parrinello, Rahman, Polymorphic transitions in single crystals: A new molecular dynamics method, Journal of Applied Physics, doi:10.1063/1.328693
Phillips, The coronavirus is here to stay -here's what that means, Nature, doi:10.1038/d41586-021-00396-2
Picarazzi, Vicenti, Saladini, Zazzi, Mori, Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge, Molecules, doi:10.3390/molecules25235695
Russo, Moccia, Spagnuolo, Tedesco, Russo, Roles of avonoids against coronavirus infection, Chem Biol Interact, doi:10.1016/j.cbi.2020.109211
Saeedi-Boroujeni, Mahmoudian-Sani, Anti-in ammatory potential of Quercetin in COVID-19 treatment, J In amm (Lond), doi:10.1186/s12950-021-00268-6
Shaldam, Yahya, Mohamed, Abdel-Daim, Al Naggar, In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes, Environ Sci Pollut Res Int, doi:10.1007/s11356-021-14195-9
Shang, Structural basis of receptor recognition by SARS-CoV-2, Nature, doi:10.1038/s41586-020-2179-y
Steinmann, Buer, Pietschmann, Steinmann, Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea, Br J Pharmacol, doi:10.1111/bph.12009
Tian, RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic, Eur J Med Chem, doi:10.1016/j.ejmech.2021.113201
Wang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res, doi:10.1038/s41422-020-0282-0
Wang, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial, The Lancet, doi:10.1016/s0140-6736(20)31022-9
Wang, Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase, Cell, doi:10.1016/j.cell.2020.05.034
Wang, Wolf, Caldwell, Kollman, Case, Development and testing of a general amber force eld, J Comput Chem, doi:10.1002/jcc.20035
Wu, A new coronavirus associated with human respiratory disease in China, Nature, doi:10.1038/s41586-020-2008-3
Yan, Architecture of a SARS-CoV-2 mini replication and transcription complex, Nat Commun, doi:10.1038/s41467-020-19770-1
Yan, Cryo-EM Structure of an Extended SARS-CoV-2 Replication and Transcription Complex Reveals an Intermediate State in Cap Synthesis, Cell, doi:10.1016/j.cell.2020.11.016
Yin, Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir, Science, doi:10.1126/science.abc1560
Yin, Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin, Nat Struct Mol Biol, doi:10.1038/s41594-021-00570-0
Zhang, Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations, ACS Cent Sci, doi:10.1021/acscentsci.1c00039
Zhao, Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2
Zhu, RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery, SLAS Discov, doi:10.1177/2472555220942123
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