Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein
Yu-Meng Chen, Jin-Lai Wei, Rui-Si Qin, Jin-Ping Hou, Guang-Chao Zang, Guang-Yuan Zhang, Ting-Ting Chen
Pharmaceutical Biology, doi:10.1080/13880209.2022.2063341
Context: Coronavirus disease 2019 is a global pandemic. Studies suggest that folic acid has antiviral effects. Molecular docking shown that folic acid can act on SARS-CoV-2 Nucleocapsid Phosphoprotein (SARS-CoV-2 N). Objective: To identify novel molecular therapeutic targets for SARS-CoV-2. Materials and methods: Traditional Chinese medicine targets and virus-related genes were identified with network pharmacology and big data analysis. Folic acid was singled out by molecular docking, and its potential target SARS-CoV-2 N was identified. Inhibition of SARS-CoV-2 N of folic acid was verified at the cellular level. Results: In total, 8355 drug targets were potentially involved in the inhibition of SARS-CoV-2. 113 hub genes were screened by further association analysis between targets and virus-related genes. The hub genes related compounds were analysed and folic acid was screened as a potential new drug. Moreover, molecular docking showed folic acid could target on SARS-CoV-2 N which inhibits host RNA interference (RNAi). Therefore, this study was based on RNAi to verify whether folic acid antagonises SARS-CoV-2 N. Cell-based experiments shown that RNAi decreased mCherry expression by 81.7% (p < 0.001). This effect was decreased by 8.0% in the presence of SARS-CoV-2 N, indicating that SARS-CoV-2 N inhibits RNAi. With increasing of folic acid concentration, mCherry expression decreased, indicating that folic acid antagonises the regulatory effect of SARS-CoV-2 N on host RNAi. Discussion and conclusions: Folic acid may be an antagonist of SARS-CoV-2 N, but its effect on viruses unclear. In future, the mechanisms of action of folic acid against SARS-CoV-2 N should be studied.
Disclosure statement The authors declare no conflicts of interest. Author contributions J.P.H. and R.S.Q. performed the bioinformatic analysis. Y.M.C. and J.L.W. wrote the paper; and T.T.C. contributed to the final version of the manuscript, as well as read and approved it; the rest of the authors contributed to the modification of the manuscript. All authors read and approved the manuscript.
References
Abike, Engin, Dunder, Tapisiz, Aslan et al., Human papilloma virus persistence and neopterin, folate and homocysteine levels in cervical dysplasias, Arch Gynecol Obstet
Acosta-Elias, Espinosa-Tanguma, The folate concentration and/or folic acid metabolites in plasma as factor for COVID-19 infection, Front Pharmacol
Akalin, Ekici, Elevli, Bucak, Aobuliaikemu et al., Traditional Chinese medicine practices used in COVID-19 (Sars-cov 2/Coronavirus-19) treatment in clinic and their effects on the cardiovascular system, Turk Kardiyol Dern Ars
Alaimo, Pulvirenti, Network-based drug repositioning: approaches, resources, and research directions, Methods Mol Biol
Aucoin, Cooley, Saunders, Cardozo, Remy et al., The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review, Adv Integr Med
Bai, Tan, Xu, Liu, Huang et al., MolAICal: a soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm, Brief Bioinform
Boyles, Yetley, Thayer, Coates, Safe use of high intakes of folic acid: research challenges and paths forward, Nutr Rev
Butterworth, Jr, Tamura, Folic acid safety and toxicity: a brief review, Am J Clin Nutr
Carlson, Asfaha, Ghent, Howard, Hartooni et al., Phosphoregulation of phase separation by the SARS-CoV-2 N Protein Suggests a Biophysical Basis for its Dual Functions, Mol Cell
Cascarina, Ross, A proposed role for the SARS-CoV-2 nucleocapsid protein in the formation and regulation of biomolecular condensates, Faseb J
Chiranjib, Ranjan, Manojit, Garima, Soo et al., COVID-19: Consider IL-6 receptor antagonist for the therapy of cytokine storm syndrome in SARS-CoV-2 infected patients, J Med Virol
Chua, Lukassen, Trump, Hennig, Wendisch et al., COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis, Nat Biotechnol
Cui, Wang, Ji, Yang, Xu et al., The nucleocapsid protein of Coronaviruses acts as a viral suppressor of RNA silencing in mammalian cells, J Virol
Deng, Wang, Wang, Kwok, High serum folate is associated with brain atrophy in older diabetic people with vitamin B12 deficiency, J Nutr Health Aging
Dinda, Dinda, Dassharma, Banik, Chakraborty et al., Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders, Eur J Med Chem
Fernandes, Mesecar, Crystallization of SARS Coronavirus 3CL protease to identify inhibitor targets, FASEB J
Flower, Buffalo, Hooy, Allaire, Ren et al., Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein, Proc Natl Acad Sci
Girija, Sivan, Ayurvedic treatment of COVID-19/SARS-CoV-2: A case report, J Ayurveda Integr Med
Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Iorio, Bosotti, Scacheri, Belcastro, Mithbaokar et al., Discovery of drug mode of action and drug repositioning from transcriptional responses, Proc Natl Acad Sci USA
Jia, Ding, Ren, Wu, Zhao et al., Effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization, Chin. J. Epidemiol
Jia, Liu, Guan, Bo, Luo et al., Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery, BMC Genomics
Kang, Yang, Hong, Zhang, Huang et al., Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites, Acta Pharm Sin B
Keum, Jeong, Development of chemical inhibitors of the SARS coronavirus: Viral helicase as a potential target, Biochem Pharmacol
Kim, Lee, Yang, Kim, Kim et al., The architecture of SARS-CoV-2 transcriptome, Cell
Li, Han, Gu, Guo, Zhang et al., Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants, Nat Commun
Li, Wang, Ren, Antiviral mechanisms of candidate chemical medicines and traditional Chinese medicines for SARS-CoV-2 infection, Virus Res
Li, Yao, Han, Yang, Chaudhry et al., Quercetin, inflammation and immunity, Nutrients
Lin, Qian, Shen, Chen, Chen et al., Computer-aided biomarker discovery for precision medicine: data resources, models and applications, Brief Bioinform
Liu, Yang, Zhang, Huang, Wang et al., Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury, Sci China Life Sci
Lokhande, Doiphode, Vyas, Swamy, Molecular docking and simulation studies on SARS-CoV-2 M(pro) reveals mitoxantrone, leucovorin, birinapant, and dynasore as potent drugs against COVID-19, J Biomol Struct Dyn
Luan, Lu, Zhang, Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection, Biochem Biophys Res Commun
Mu, Xu, Zhang, Shu, Wu et al., SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells, Sci China Life Sci
Quirch, Lee, Shabnam, Hazards of the cytokine storm and cytokine-targeted therapy in Patients With COVID-19: Review, J Med Internet Res
Schaecher, Stabenow, Oberle, Schriewer, Buller et al., An immunosuppressed Syrian golden hamster model for SARS-CoV infection, Virology
Sekimukai, Iwata-Yoshikawa, Fukushi, Tani, Kataoka et al., Gold nanoparticle-adjuvanted S protein induces a strong antigen-specific IgG response against severe acute respiratory syndrome-related coronavirus infection, but fails to induce protective antibodies and limit eosinophilic infiltration in lungs, Microbiol Immunol
Sen-Nan, Li, Yuan-Yuan, Wei-Feng, Jia et al., Material basis and mechanism of Erzhi pill for preventing osteoporosis based on network pharmacology, Chi Pharm J
Shan, Qiaozhen, Digvijay, Cao, Diedrich et al., The SARS-CoV-2 Nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein, Nature Commun
Simanjuntak, Ko, Lee, Yu, Lin, Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice, PLoS Pathog
Singh, Singh, Singh, Misra, Molnupiravir in COVID-19: A systematic review of literature, Diabetes Metab Syndr
Siu, Yuen, Castano-Rodriguez, Ye, Yeung et al., Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC, Faseb J
Skariyachan, Gopal, Chakrabarti, Kempanna, Uttarkar et al., Structural and molecular basis of the interaction mechanism of selected drugs towards multiple targets of SARS-CoV-2 by molecular docking and dynamic simulation studies-deciphering the scope of repurposed drugs, Comput Biol Med
Uribe-Diaz, Nazeer, Jaime, Vargas-Berm Udez, Yitbarek et al., Folic acid enhances proinflammatory and antiviral molecular pathways in chicken B-lymphocytes infected with a mild Infectious Bursal disease virus, Br Poult Sci. In Press
Vaishali, Prakash, Sibi, Ramesh, Brijesh et al., Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2, J Biomol Struct Dyn
Wang, Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study, J Chem Inf Model
Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science
Wu, Zhao, Yu, Chen, Song et al., A new coronavirus associated with human respiratory disease in China, Nature
Xiaoqing, Xin, Tingting, Chuanke, Yongxiang et al., Strand antagonism in RNAi: an explanation of differences in potency between intracellularly expressed siRNA and shRNA, Stud. Trace Elem. Health
Yoshimoto, The proteins of severe acute respiratory syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the cause of COVID-19, Protein J
Zhang, Xue, Wang, Zhao, Li et al., Network-based drug repositioning: A novel strategy for discovering potential antidepressants and their mode of action, Eur Neuropsychopharmacol
Zheng, Wu, Gu, Weng, Wang et al., Modular characteristics and mechanism of action of herbs for endometriosis treatment in Chinese medicine: A data mining and network pharmacology-based identification, Front Pharmacol
Zhu, Wei, Sun, Development of vaccines against COVID-19, Prev Med
Zsuzsanna, Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients, J Pharm Sci
