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Protease Inhibitors: Saquinavir and Boceprevir

The COVID-19 pandemic continues to cause death and severe illness around the world. As many countries still experience vaccine shortages and the virus evolves to be more contagious, we need to develop better treatments for this disease.

A Possible Target:

The SARS-CoV2 main protease (Mpro) is an attractive target for drug treatment. The coronavirus needs this protease to process its proteins, an important step in its life cycle. Protease inhibitors are already in clinical use to treat other viral infections, such as HIV and hepatitis C. Repurposed existing drugs can get approval to treat disease faster than new drugs because their safety and pharmacokinetics are already known. Can we repurpose known protease inhibitors to treat SARS-CoV2 infection?

Two recent scientific studies address this question.

Docking and Molecular Dynamics Simulations:

Bello et al. built a computer model of Mpro and twelve promising protease inhibitors: darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin, and bortezomib. The model predicts that of the twelve, saquinavir should bind to Mpro the best. Interestingly, saquinavir has long been used as part of drug cocktails to treat HIV. Although a computer study is limited, saquinavir is worth following up in vitro.

Enzyme Assays:

Another team of researchers, Ma et al., used an enzyme assay to screen for drugs that might inhibit the activity of Mpro. Out of a library of known inhibitors, they found that boceprevir inhibited Mpro the most. Formerly, boceprevir was used to treat hepatitis C before more effective protease inhibitors were developed. Boceprevir might find new life now as a treatment for COVID-19, and is worth further study.

 

Bello M, Martinez-Muñoz A, Balbuena-Rebolledo I. Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA. Journal of Molecular Modeling. 2020 Nov 12; 26(12):340. PMID: 33184722

Ma C, Sacco MC, Hurst B, et al. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV2 viral replication by targeting the viral main protease. Cell Research. 2020 Aug; 30(8):678-692. PMID: 32541865

Remdesivir Synergy Against COVID-19

Currently, remdesivir is the only antiviral drug approved to treat COVID-19. Its effects on the course of disease are moderate. Many viral diseases, such as HIV and hepatitis C, are treated with drug cocktails. Existing antiviral drugs might make remdesivir more effective in combination.

Two research teams recently screened for antiviral drugs that might increase the effectiveness of remdesivir.

Lo et al. screened a library of drugs for its ability to reduce SARS-CoV-2 viral load in kidney epithelial cells. They found that simeprevir reduces viral load in vitro. Simeprevir is a protease inhibitor that is often combined with sofosbuvir to treat hepatitis C. Simeprevir was even more effective in the in vitro experiment when combined with remdesivir.

Nguyenla et al. added remdesivir to cell cultures of kidney epithelial cells and human lung cells and infected these cells with SARS-CoV-2. They used this remdesivir-treated culture to screen a large library of FDA-approved drugs for compounds that reduce a proxy measure of viral load. The team chose the twenty most promising drugs to validate in human lung cell culture, which they tested for viral load.

The drugs velpatasvir and elbasvir reduced viral load. Both velpatasvir and elbasvir are used as parts of drug cocktails to treat hepatitis C. Velpatasvir is used with sofosbuvir and elbasvir is used with grazoprevir. The research team then tested the velpatasvir/sofosbuvir and elbasvir/grazoprevir cocktails with remdesivir in lung cell culture; the three-drug cocktails were even more effective that the pairs.

These results support the idea that COVID-19 could be better treated with cocktails of antiviral drugs.

 

Lo HS, Hui KPY, Lai HM, et al. Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir. ACS Central Science. 2021 May 26;7(5): 792-802. doi: 10.1021/acscentsci.0c01186. PMID: 34075346

Nguyenla X, Wehri E, Dis EV, et al. Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells. BiorXiv. Preprint. 2020 Sept. http://doi.org/10.1101/2020.09.18.302398