Virus World

A team of scientists from the United States has recently revealed that small molecule inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease exhibit potent antiviral activity. These inhibitors show better efficacy when used in combination with antiviral medicine Remdesivir. The study is currently available on the bioRxiv* preprint server.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19) pandemic, is a positive-sense RNA virus with a genome size of about 30 kb. The virus spread rapidly from person to person, primarily via respiratory droplets. Since its emergence in December 2019 in China, the deadly SARS-CoV-2 has infected more than 40 million people and claimed more than 1 million lives globally. Currently, no antiviral medication or vaccine is available to specifically and effectively treat SARS-CoV-2 infection.The SARS-CoV-2 genome encodes several structural and non-structural proteins, and many of these proteins are currently under investigation as potential antiviral targets. One such example is 3-chymotrypsin-like protease or main protease, which is a non-structural SARS-CoV-2 protein required for viral replication. Small molecule inhibitors of viral main protease, including boceprevir, calpain inhibitors II and XII, and GC-376, have been shown to inhibit SARS-CoV-2 replication in vitro assays. The crystal structure analysis studies have shown that these compounds stably and strongly interact with viral main protease.

Interestingly, calpain inhibitors II and XII exhibit more potent antiviral effects than GC-376, despite having weaker inhibitory effects against SARS-CoV-2 main protease. In in vitro setups, calpain inhibitors II and XII have been found to inhibit human cathepsin L.  Given these observations, the current study scientists hypothesized that stronger antiviral activities of calpain inhibitors II and XII may be attributed to their ability to inhibit host cathepsin L, which is known to facilitate the entry of SARS-CoV-2 into cells by cleaving and activating the viral spike protein. The scientists conducted pseudovirus neutralization assay and drug time-of-addition assay to investigate whether calpain inhibitors II and XII are capable of inhibiting both viral main protease and host cathepsin L. Moreover, they determined the antiviral efficacy of boceprevir, calpain inhibitors II and XII, and GC-376 against a group of human coronaviruses, including highly infectious SARS-CoV-1 and Middle-East respiratory syndrome coronavirus (MERS-CoV) and seasonal HCoV-OC43, HCoV-NL63, and HCoV-229E. They also tested the efficacy of these compounds in combination with antiviral medicine Remdesivir. ..

Preprint of study in biopRxiv (November 1, 2020):

https://doi.org/10.1101/2020.10.30.362335

Anticoagulants are associated with clinical benefit against the 2019 coronavirus disease (COVID-19), preventing COVID-19 associated coagulopathy. Blood coagulation factor Xa (FXa) and SARS-CoV-2 major protease (Mpro) share over 80% homology at the three-dimensional protein level. Thus, it is worth interrogating whether there is crosstalk between inhibitors and substrates between these enzymes. Here, we found that the clinically-approved FXa inhibitor apixaban targets SARS-CoV-2 Mpro with a 21-fold higher potency than boceprevir (GC376). Apixaban displayed a non-competitive mechanism of inhibition towards Mpro, since it targets the enzyme/substrate complex and the allosteric site onto the viral protease. Enzymatic assays were further validated in infected Calu-3 cells, which reveal that apixaban decreases the production of infectious viral particles in a dose-dependent manner, with an inhibitory potency in the micromolar range. Our results are in line with the proposed early use of anticoagulants, including FXa inhibitors, to improve clinical outcome of COVID-19 patients. In this context, apixaban may display a dual mechanism of action by targeting FXa to prevent coagulopathy and, at some level, SARS-CoV-2 Mpro.

Available at bioRxiv (Sept. 24, 2021):

https://doi.org/10.1101/2021.09.23.461605