Antiviral drugs have been proven successful as a therapeutic approach to inhibit HCV and HIV viral proteases. With the coronavirus disease 2019 (COVID-19) pandemic causing unprecedented morbidity and mortality, there is an urgent need for effective antivirals to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, scientists across the world have been trying to repurpose existing antivirals designed to treat other viruses.
Remdesivir, a nucleotide analog that inhibits the nsp12 polymerase and originally developed for Ebola, was approved to treat SARS (or SARS-CoV-1) as a result of these drug repurposing efforts. Another nsp12 inhibitor, MK-4482/EIDD-2801, is currently being assessed for use in SARS-CoV-2 therapy.
SARS-CoV-2 main protease, 3CLpro, is a promising target for antiviral drugs
The SARS-CoV-2 main protease, 3-chymotrypsin-like cysteine protease (Mpro, 3CLpro), is a promising target for antiviral drugs with no human homolog. PF-07304814, a phosphate prodrug of PF-00835231, is the most advanced drug candidate that currently targets the SARS-CoV-2 3CLpro. It was discovered over 15 years ago during the SARS-CoV-1 outbreak.
Cathepsin L plays a role in SARS-CoV-2 entry into host cells and thus contributes to non-selective 3CLpro inhibition in common cell lines. Although there have been several reports of potent in vitro 3CLpro inhibitors of SARS-CoV-2, some of these compounds lack selectivity, especially vs. cathepsin L. This suggests an overestimation of the 3CLpro component of in vitro cellular potency and its translation into in vivo activity, thus raising safety and efficacy concerns.
A structure-based approach that monitors cathepsin L and SARS-CoV-2 3CLpro inhibition
A team of researchers from the US and Belgium applied a structure-based approach with early monitoring of cathepsin L inhibition along with SARS-CoV-2 3CLpro inhibition. They identified a potent and selective SARS-CoV-2 3CLpro inhibitor, ALG-097111, which has proven activity against SARS-CoV-2 in SARS-CoV-2 hamster models in vivo. This study is published in the journal, Biochemical and Biophysical Research Communications.
ALG-097111 strongly inhibits SARS-CoV-2 3CLpro without affecting cathepsin L activity
The results of the study showed that ALG-097111 strongly inhibited SARS-CoV-2 3CLpro without affecting cathepsin L activity. In hamsters infected with SARS-CoV-2, ALG-097111 induced a potent and significant reduction in the viral RNA copies and infectious virus titers in the lungs. According to the authors, these findings offer in vivo validation for the role of SARS-CoV-2 3CLpro as a key therapeutic target for selective small molecule inhibitors.
In conclusion, ALG-097111, a selective SARS-CoV-2 3CLpro inhibitor, is a potent inhibitor of the in vitro replication of SARS-CoV-2 and efficiently inhibits viral replication in the lungs of infected hamsters.”
To summarize, the selective SARS-CoV-2 3CLpro inhibitor, ALG-097111, is a strong inhibitor of SARS-CoV-2 replication in vitro. It also efficiently inhibits viral replication in the lungs of SARS-CoV-2-infected hamsters.
The authors mentioned that this is the first demonstration of a selective SARS-CoV-2 3CLpro inhibitor without an inhibitory effect on cathepsin L activity showing a pronounced inhibitory effect on viral replication in an animal model. Future studies need to focus on investigating compound dosing in a therapeutic setting and combinations of other modalities against SARS-CoV-2.
The team concludes:
To the best of our knowledge, this is the first time that a selective SARS-CoV-2 3CLpro inhibitor (i.e., without a significant inhibitory effect on cathepsin L activity), has been shown to result in such a pronounced inhibitory effect on SARS-CoV-2 replication in an animal infection model.”