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  3. Erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin inhibit cytopathic effect, papain-like protease, and MPRO enzymes of SARS-CoV-2

Erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin inhibit cytopathic effect, papain-like protease, and MPRO enzymes of SARS-CoV-2

  • Front Cell Infect Microbiol. 2023 Nov 27:13:1273982. doi: 10.3389/fcimb.2023.1273982.
Shaibu Oricha Bello 1 2 3,  Mustapha Umar Imam 3 4,  Muhammad Bashir Bello 3 5,  Abdulmajeed Yunusa 1 3,  Adamu Ahmed Adamu 1 3,  Abdulmalik Shuaibu 3 5,  Ehimario Uche Igumbor 2 6,  Zaiyad Garba Habib 2 7,  Mustapha Ayodele Popoola 2,  Chinwe Lucia Ochu 2 8,  Aishatu Yahaya Bello 9,  Yusuf Yahaya Deeni 2 10 11,  Ifeoma Okoye 12
Affiliations

Affiliations

  • 1 Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
  • 2 Nigerian COVID-19 Research Coalition, Nigerian Institute of Medical Research Institute, Lagos, Nigeria.
  • 3 Centre for Advanced Medical Research and Training, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
  • 4 Department of Medical Biochemistry, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
  • 5 Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Usmanu Danfodiyo University, Sokoto, Nigeria.
  • 6 School of Public Health, University of the Western Cape, Cape Town, South Africa.
  • 7 Department of Medicine, University of Abuja Teaching Hospital, Abuja, Nigeria.
  • 8 Nigerian Centre for Disease Control and Prevention, Abuja, Nigeria.
  • 9 Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
  • 10 Department of Microbiology and Biotechnology, Federal University of Dutse, Dutse, Nigeria.
  • 11 Centre for Environmental and Public Health Research and Development, Kano, Nigeria.
  • 12 University of Nigeria Centre for Clinical Trials, University of Nigeria Teaching Hospital, Enugu, Nigeria.
PMID: 38089816 DOI: 10.3389/fcimb.2023.1273982
Abstract

Background: Although tremendous success has been achieved in the development and deployment of effective COVID-19 vaccines, developing effective therapeutics for the treatment of those who do come down with the disease has been with limited success. To repurpose existing drugs for COVID-19, we previously showed, qualitatively, that erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin inhibit SARS-COV-2-induced cytopathic effect (CPE) in Vero cells.

Aim: This study aimed to quantitatively explore the inhibition of SARS-CoV-2-induced CPE by erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin and to determine the effect of these drugs on SARS-CoV-2 papain-like protease and 3CL protease (MPRO) Enzymes.

Methods: Neutral red (3-amino-7-dimethylamino-2-methyl-phenazine hydrochloride) cell viability assay was used to quantify CPE after infecting pre-treated Vero cells with clinical SARS-Cov-2 isolates. Furthermore, SensoLyte® 520 SARS-CoV-2 papain-like protease and SensoLyte® 520 SARS-CoV-2 MPRO activity assay kits were used to evaluate the inhibitory activity of the drugs on the respective Enzymes.

Results: Erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin dose-dependently inhibit SARS-CoV-2-induced CPE in Vero cells, with inhibitory concentration-50 (IC50) values of 3.27 µM, 4.23 µM, 9.29 µM, 3.19 µM, and 84.31 µM, respectively. Furthermore, erythromycin, retapamulin, pyridoxine, folic acid, and ivermectin dose-dependently inhibited SARS-CoV-2 papain-like protease with IC50 values of 0.94 µM, 0.88 µM, 1.14 µM, 1.07 µM, and 1.51 µM, respectively, and inhibited the main protease (MPRO) with IC50 values of 1.35 µM, 1.25 µM, 7.36 µM, 1.15 µM, and 2.44 µM, respectively.

Conclusion: The IC50 for all the drugs, except ivermectin, was at the clinically achievable plasma concentration in humans, which supports a possible role for the drugs in the management of COVID-19. The lack of inhibition of CPE by ivermectin at clinical concentrations could be part of the explanation for its lack of effectiveness in clinical trials.

Keywords

COVID-19; SARS-CoV-2; erythromycin; folic acid; ivermectin; pyridoxine; retapamulin.

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