Anti-HIV drug repurposing against SARS-CoV-2

Sang, Peng; Tian, Shu-Hui; Meng, Zhen; Yang, Liquan

doi:10.1039/d0ra01899f

Cited by 88 publications

(73 citation statements)

References 31 publications

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“… 240 In this case, ritonavir, lopinavir, and darunavir (anti-HIV drugs) were considered, and it was finally suggested that darunavir should be more selective for recognizing PLpro instead of 3CLpro. Nevertheless, additional docking studies suggest that darunavir could also be a suitable choice to bind 3CLpro, 241 , 242 highlighting the relevance of this particular anti-HIV drug as a potential anti-COVID-19 clinical drug.…”

Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.

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Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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“…Furthermore, it has been recently reported that nelfinavir had anti-SARS-CoV-2 activity, as demonstrated in a cell-based experimental assay [12,13]. In addition, other HIV protease inhibitors such as indinavir, darunavir, and saquinavir, have been proposed as drug candidates against SARS-CoV-2 M pro , using computational studies [14][15][16][17][18]. These HIV protease inhibitors are repurposed drug candidates, some of which are already being tested in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…For a detailed comparison of the binding affinity among ligands, an estimation of the precise proteinligand complex structure is crucial and can be achieved by MD simulations with longer duration. Recently, several studies on promising inhibitors of M pro system, using molecular docking and MD simulations, have been reported[14][15][16][17][18]25,26]. These studies proposed several HIV-1 protease inhibitors as promising inhibitor candidates of M pro .…”

mentioning

confidence: 99%

Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

Komatsu¹,

Okimoto²,

KOYAMA³

et al. 2020

Preprint

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<div> <div> <div> <p>We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations. <br></p><p><br></p><p><br> </p><div> <div> <div> <p>Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.<br></p> </div> </div> </div> </div> </div> </div>

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“…To our knowledge, direct determination of the inhibition e cacy of HIV PIs against SARS-CoV-2 M pro in cell culture has not yet been attempted, although many in silico studies analyzing interaction between SARS-CoV-2 M pro and potential inhibitors were published [20][21][22][23][24][25][26] (Supplementary Table 1). Antiviral assays using lopinavir and ritonavir in Calu-3 cells were previously carried out for MERS-CoV, and the IC 50 for lopinavir, ritonavir and their combination was 11.6, 24.9, and 8.5 µM respectively [3].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

Mahdi

Mótyán

Szojka

et al. 2020

Preprint

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Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. Atazanavir on the other hand was the only PI to inhibit the viral protease both in cell culture and in our in vitro enzymatic assay. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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Anti-HIV drug repurposing against SARS-CoV-2

Abstract: A novel severe acute respiratory syndrome human coronavirus (SARS HCoV) was identified from respiratory illness patients (named SARS-CoV-2 by ICTV) in December 2019 and has recently emerged as a serious threat to world public health.

Cited by 88 publications

References 31 publications

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

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