Hepatitis C virus drugs synergize with remdesivir against SARS-CoV-2 in vitro

By Dr. Ramya Dwivedi, Ph.D.Dec 17 2020

SARS-CoV-2 has infected over 71.5 million people and claimed over 1.6 million lives globally since December 2019. The mitigation strategies implemented worldwide have slowed down the pace of this pandemic.

The unprecedented development of a vaccine has also been successfully achieved. Currently, people have started receiving the vaccine shots. However, an effective therapeutic drug against SARS-CoV-2 is still not available for patients in clinics.

The current urgency for an effective antiviral drug against SARS-CoV-2 cannot wait for a lengthy approval process for potential drug candidates. Keeping this in view, Bafna, White, and colleagues try several available hepatitis C virus (HCV) drugs against SARS-CoV-2 and find that these drugs inhibit the SARS-CoV-2 Mpro and/or PLproproteases and SARS-CoV-2 replication in cell culture.

In this study, the researchers identify two drugs, simeprevir, and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold.

Graphical Abstract. Image Credit: https://www.biorxiv.org/content/10.1101/2020.12.13.422511v1.full.pdf

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Due to a striking structural similarity between the SARS-CoV-2 proteases and the HCV proteases, the researchers assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. The observations of this study are published recently in a bioRxiv* preprint server.

They find that these are effective inhibitors and work synergistically with the anti-SARS-CoV-2 drug remdesivir in cell culture studies. Remdesivir is used as a drug against SARS-CoV-2 in some patients; it inhibits the viral RNA-dependent RNA polymerase. It is the current FDA-approved antiviral for COVID-19 (coronavirus disease 2019).

The SARS-CoV-2 virus contains a single, large positive-sense single-stranded RNA as the genetic material, which is directly translated by host cell ribosomes. It encodes 4 structural proteins, 16 non-structural proteins (NSPs) with crucial intracellular functions, and 9 accessory proteins.

The 16 NSPs are processed by two virus-encoded cysteine proteases, the papain-like protease (PLpro) and a 3C-like protease (3CLpro 6), also referred to as the main protease (Mpro). These two proteases are essential for the virus life cycle. These are involved in the production of a functional viral RNA polymerase. They generate replication organelles, or the double-membrane vesicles, required for the function of the viral RNA polymerase.

Because of the similar structural architecture of SARS-CoV-2 Mpro and the HCV protease, the researchers initiated a search for the drug candidate among the available HCV protease inhibitor drugs. They identified ten HCV protease inhibitors predicted by the striking similarity of the substrate-binding clefts of the SARS-CoV-2 Mpro and HCV proteases. These inhibitors docked snuggly into the substrate-binding cleft of Mpro.

In this study, they show that:

1. four HCV drugs, boceprevir, narlaprevir, telaprevir, and vaniprevir strongly inhibit the SARS-CoV-2 Mpro protease activity;
2. three HCV drugs, grazoprevir, simeprevir, and asunaprevir moderately inhibit Mpro activity;
3. four HCV drugs, simeprevir, grazoprevir, vaniprevir, and paritaprevir inhibit PLpro protease activity; and
4. vaniprevir is the only one of the tested HCV drugs that strongly inhibits both Mpro and PLpro.

HCV drugs that inhibit Mpro and/or PLpro would be expected to inhibit viral RNA polymerase function in infected cells by inhibiting the generation of protein subunits of the viral polymerase and/or by inhibiting the generation of the integral-membrane non-structural viral proteins that form the replication organelles (double-membrane vesicles) required for polymerase function.”

The researchers found that the inhibitory effects were additive or synergistic depending on the HCV drug used to inhibit virus replication. They report that boceprevir and vaniprevir (which strongly inhibits the protease) act additively with remdesivir to inhibit virus replication, whereas simeprevir and grazoprevir, (which moderately/strongly inhibits) act synergistically with remdesivir.

The basis for the different interactions between remdesivir and in particular the HCV drugs, and the mechanism(s) of synergy, needs to be further explored, the researchers write.

Repurposing drugs and using them in combination may achieve clinical efficacy. Further research and assessment of this study are warranted for use in the successful treatment of COVID-19 patients. In this study, several HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro and PLpro.

The researchers identify seven HCV drugs that inhibit virus replication in Vero and/or human 293T cells expressing the ACE2 receptor. They show that HCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS-CoV-2 replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. They also recommend simeprevir as a repurposed drug because it effectively inhibits SARS-CoV-2 virus replication in the human cells at much lower concentrations than grazoprevir.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources