Chlorpheniramine Maleate Displays Multiple Modes of Antiviral Action Against SARS-CoV-2: A Mechanistic Study
Yaseen A M M Elshaier, Ahmed Mostafa, Fernando Valerio-Pascua, Mari L Tesch, Joshua M Costin, M.D, M.H.S Franck F Rahaghi
Chlorpheniramine Maleate (CPM) has been identified as a potential antiviral compound against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In this study, we investigated the in vitro effects of CPM on key stages of the SARS-CoV-2 replication cycle, including viral adsorption, replication inhibition, and virucidal activity. Our findings demonstrate that CPM exhibits antiviral properties by interfering with viral adsorption, replication, and directly inactivating the virus. Molecular docking analysis revealed interactions between CPM and essential viral proteins, such as the main protease receptor, spike protein receptor, and RNA polymerase. CPM's interactions were primarily hydrophobic in nature, with an additional hydrogen bond formation in the RNA polymerase active site. These results suggest that CPM has the potential to serve as a multitarget antiviral agent against SARS-CoV-2 and potentially other respiratory viruses. Further investigations are warranted to explore its clinical implications and assess its efficacy in vivo.
References
Ahmad, Pawara, Surana, Patel, The Repurposed ACE2 Inhibitors: SARS-CoV-2 Entry Blockers of Covid-19, Top Curr Chem (Cham)
Allam, Assaf, Hassan, Shimizu, Elshaier, An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19 [10.1039/D0RA05265E, RSC Advances,
doi:10.1039/D0RA05265E
Black, Molecular Modeling and Preliminary Clinical Data Suggesting Antiviral Activity for Chlorpheniramine (Chlorphenamine) Against COVID-19, Cureus,
doi:10.7759/cureus.20980
Blanco, Bonilla, Homma, Suzuki, Fremont-Smith et al., Antihistamines and azithromycin as a treatment for COVID-19 on primary health care -A retrospective observational study in elderly patients, Pulm Pharmacol Ther,
doi:10.1016/j.pupt.2021.101989
Feoktistova, Geserick, Leverkus, Crystal Violet Assay for Determining Viability of Cultured Cells, Cold Spring Harb Protoc,
doi:10.1101/pdb
Gies, Bekaddour, Dieudonné, Guffroy, Frenger et al., Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine, Front Immunol,
doi:10.3389/fimmu.2020.01409
Jabeen, Pleban, Rinner, Chiba, Ecker, Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P-glycoprotein, J Med Chem,
doi:10.1021/jm201705f
Kandeil, Mostafa, El-Shesheny, Shehata, Roshdy et al., Coding-Complete Genome Sequences of Two SARS-CoV-2 Isolates from Egypt, Microbiol Resour Announc
Kuo, Lin, Tsai, Chou, Kung et al., Samarangenin B from Limonium sinense suppresses herpes simplex virus type 1 replication in Vero cells by regulation of viral macromolecular synthesis, Antimicrob Agents Chemother,
doi:10.1128/aac.46.9.2854-2864.2002
Mosmann, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J Immunol Methods,
doi:10.1016/0022-1759(83)90303-4
Mostafa, Kandeil, Kutkat, Moatasim, Rashad et al., FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2, Pharmaceuticals,
doi:10.3390/ph13120443
Mostafa, Kandeil, Shehata, El Shesheny, Samy et al., Middle East Respiratory Syndrome Coronavirus (MERS-CoV): State of the Science, Microorganisms
Reznikov, Norris, Vashisht, Bluhm, Li et al., Identification of antiviral antihistamines for COVID-19 repurposing, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2020.11.095
Rizvi, Ferrer, Khawaja, Sanchez-Gonzalez, Chlorpheniramine, an Old Drug with New Potential Clinical Applications: A Comprehensive Review of the Literature, Current Reviews in Clinical and Experimental Pharmacology,
doi:10.2174/2772432817666220601162006
Sanchez-Gonzalez, Rizvi, Torres, Ferrer, A Randomized Controlled Pilot Trial to Test the Efficacy of Intranasal Chlorpheniramine Maleate With Xylitol for the Treatment of Allergic Rhinitis, Cureus,
doi:10.7759/cureus.14206
Sanchez-Gonzalez, Westover, Rizvi, Torres, Ferrer, Intranasal Chlorpheniramine Maleate for the treatment of COVID-19: Translational and Clinical Evidence, Medical Research Archives,
doi:10.18103/mra.v10i3.2752
Schuhmacher, Reichling, Schnitzler, Virucidal effect of peppermint oil on the enveloped viruses herpes simplex virus type 1 and type 2 in vitro, Phytomedicine,
doi:10.1078/094471103322331467
Torres, Go, Camacho, Sanchez-Gonzalez, Ferrer, Chlorpheniramine Maleate Nasal Spray In COVID-19 Patients: Case Series, J Clin Exp Pharmacol,
doi:10.35248/2161-1459.21.10.275
Towler, Staker, Prasad, Menon, Tang et al., ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis, J Biol Chem
Valerio-Pascua, Mejia, Tesch, Godoy, Fuentes et al., Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials
Westover, Ferrer, Vazquez, Bethencourt-Mirabal, Go, In Vitro Virucidal Effect of Intranasally Delivered Chlorpheniramine Maleate Compound Against Severe Acute Respiratory Syndrome Coronavirus 2, Cureus,
doi:10.7759/cureus.10501
Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science,
doi:10.1126/science
Xu, Xia, Pu, Wang, Li et al., The Antihistamine Drugs Carbinoxamine Maleate and Chlorpheniramine Maleate Exhibit Potent Antiviral Activity Against a Broad Spectrum of Influenza Viruses, Front Microbiol,
doi:10.3389/fmicb.2018.02643
Zhang, Zhan, Yao, Gao, Shong, Antiviral activity of tannin from the pericarp of Punica granatum L. against genital Herpes virus in vitro, Zhongguo Zhong Yao Za Zhi
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