In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach

Maria I. Zapata-Cardona; Lizdany Florez-Alvarez; Ariadna L. Guerra-Sandoval; Mateo Chvatal-Medina; Carlos M. Guerra-Almonacid; Jaime Hincapie-Garcia; Juan C. Hernandez; Maria T. Rugeles; Wildeman Zapata-Builes; Maria I. Zapata-Cardona; Lizdany Florez-Alvarez; Ariadna L. Guerra-Sandoval; Mateo Chvatal-Medina; Carlos M. Guerra-Almonacid; Jaime Hincapie-Garcia; Juan C. Hernandez; Maria T. Rugeles; Wildeman Zapata-Builes

doi:10.3934/microbiol.2023002

AIMS Microbiology

2023, Volume 9, Issue 1: 20-40. doi: 10.3934/microbiol.2023002

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Research article Topical Sections

In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach

1.
Grupo Inmunovirologia, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia
2.
Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
3.
Grupo de investigacion GIRYSOUT, Universidad del Tolima, Ibague, Colombia
4.
Grupo de investigacion, Promocion y prevencion farmaceutica, Facultad de ciencias farmaceuticas yalimentarias, Universidad de Antioquia UdeA, Medellin, Colombia
5.
Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellin, Colombia

Received: 05 September 2022 Revised: 26 November 2022 Accepted: 13 December 2022 Published: 16 January 2023

Background
Drug repurposing is a valuable strategy for rapidly developing drugs for treating COVID-19. This study aimed to evaluate the antiviral effect of six antiretrovirals against SARS-CoV-2 in vitro and in silico.
Methods
The cytotoxicity of lamivudine, emtricitabine, tenofovir, abacavir, efavirenz and raltegravir on Vero E6 was evaluated by MTT assay. The antiviral activity of each of these compounds was evaluated via a pre-post treatment strategy. The reduction in the viral titer was assessed by plaque assay. In addition, the affinities of the antiretroviral interaction with viral targets RdRp (RNA-dependent RNA polymerase), ExoN-NSP10 (exoribonuclease and its cofactor, the non-structural protein 10) complex and 3CLpro (3-chymotrypsin-like cysteine protease) were evaluated by molecular docking.
Results
Lamivudine exhibited antiviral activity against SARS-CoV-2 at 200 µM (58.3%) and 100 µM (66.7%), while emtricitabine showed anti-SARS-CoV-2 activity at 100 µM (59.6%), 50 µM (43.4%) and 25 µM (33.3%). Raltegravir inhibited SARS-CoV-2 at 25, 12.5 and 6.3 µM (43.3%, 39.9% and 38.2%, respectively). The interaction between the antiretrovirals and SARS-CoV-2 RdRp, ExoN-NSP10 and 3CLpro yielded favorable binding energies (from −4.9 kcal/mol to −7.7 kcal/mol) using bioinformatics methods.
Conclusion
Lamivudine, emtricitabine and raltegravir showed in vitro antiviral effects against the D614G strain of SARS-CoV-2. Raltegravir was the compound with the greatest in vitro antiviral potential at low concentrations, and it showed the highest binding affinities with crucial SARS-CoV-2 proteins during the viral replication cycle. However, further studies on the therapeutic utility of raltegravir in patients with COVID-19 are required.
- antiretrovirals,
- SARS-CoV-2,
- COVID-19,
- molecular docking,
- drug repurposing
Citation: Maria I. Zapata-Cardona, Lizdany Florez-Alvarez, Ariadna L. Guerra-Sandoval, Mateo Chvatal-Medina, Carlos M. Guerra-Almonacid, Jaime Hincapie-Garcia, Juan C. Hernandez, Maria T. Rugeles, Wildeman Zapata-Builes. In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach[J]. AIMS Microbiology, 2023, 9(1): 20-40. doi: 10.3934/microbiol.2023002

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Abstract

Background

Drug repurposing is a valuable strategy for rapidly developing drugs for treating COVID-19. This study aimed to evaluate the antiviral effect of six antiretrovirals against SARS-CoV-2 in vitro and in silico.

Methods

The cytotoxicity of lamivudine, emtricitabine, tenofovir, abacavir, efavirenz and raltegravir on Vero E6 was evaluated by MTT assay. The antiviral activity of each of these compounds was evaluated via a pre-post treatment strategy. The reduction in the viral titer was assessed by plaque assay. In addition, the affinities of the antiretroviral interaction with viral targets RdRp (RNA-dependent RNA polymerase), ExoN-NSP10 (exoribonuclease and its cofactor, the non-structural protein 10) complex and 3CLpro (3-chymotrypsin-like cysteine protease) were evaluated by molecular docking.

Results

Lamivudine exhibited antiviral activity against SARS-CoV-2 at 200 µM (58.3%) and 100 µM (66.7%), while emtricitabine showed anti-SARS-CoV-2 activity at 100 µM (59.6%), 50 µM (43.4%) and 25 µM (33.3%). Raltegravir inhibited SARS-CoV-2 at 25, 12.5 and 6.3 µM (43.3%, 39.9% and 38.2%, respectively). The interaction between the antiretrovirals and SARS-CoV-2 RdRp, ExoN-NSP10 and 3CLpro yielded favorable binding energies (from −4.9 kcal/mol to −7.7 kcal/mol) using bioinformatics methods.

Conclusion

Lamivudine, emtricitabine and raltegravir showed in vitro antiviral effects against the D614G strain of SARS-CoV-2. Raltegravir was the compound with the greatest in vitro antiviral potential at low concentrations, and it showed the highest binding affinities with crucial SARS-CoV-2 proteins during the viral replication cycle. However, further studies on the therapeutic utility of raltegravir in patients with COVID-19 are required.

Abbreviations

PDB ID

Protein Data Bank identification code

RdRp

RNA-dependent RNA polymerase

ExoN-NSP10

Exoribonuclease and its cofactor, the non-structural protein 10 complex

3CLpro

3-chymotrypsin-like cysteine protease

Acknowledgments

We want to thank to Instituto Nacional de Salud, Bogota-Colombia, for donating the Vero E6 cell line.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study was supported by Universidad de Antioquia (strategy # UdeA responde al COVID-19), CODI (Act 2020–36850) and Universidad Cooperativa de Colombia. BPIN 2020000100131-SGR.

Author contributions

Study conception and design: MTR, WZB, CGA, AGS, JHG and JCH. Data collection, analysis and interpretation of results: MZC, LFA and AGS Draft manuscript preparation: MZC, LFA, AGS and MMC. Assistance with interpretation of the results and manuscript writing: MTR, WZB, CGA, JHG and JCH. Guide and review research: MTR and WZB. All authors have contributed to editing this paper; they have approved this final submission.

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