ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model

Abstract

There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic. The SARS-CoV-2 main protease (3CLpro) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro (IC 50 = 7 nM) without affecting the activity of human cathepsin L (IC 50 > 10 μM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log 10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log 10 (TCID 50 /mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro as a promising therapeutic target for selective small molecule inhibitors.

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

“…This compound is administered to hospitalized patients via intravenous infusion. Several protease inhibitors are also under investigation that can be provided as oral therapies to nonhospitalized populations [ 42 ].…”

Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters

“…Overall, we demonstrate that hamsters can serve as relevant preclinical model that can be used to assess the infectivity of clinical SARS-CoV-2 isolates including that of current VoC. This model will also serve as an important tool to study the efficacy of current and future vaccines [ 17 , 21 , 22 ] and therapies [ 16 , 23 ].…”

SARS-CoV-2 Antiviral Therapy

“…These compounds belong to several families of reversible and covalently binding peptidomimetic inhibitors, many of which have been cocrystallized with SARS-CoV-2 Mpro ( 81 , 91 – 97 ). These compounds are of interest as chemical scaffolds for potential therapeutic agents; however, some of these compounds may not be sufficiently selective for Mpro, increasing their risk of off-target effects ( 98 , 99 ). In addition, most current inhibitors bind Mpro covalently, which also increases the risk of off-target effects ( 80 ).…”