Data Bytes: coronavirus-targeted small molecules
The SARS-CoV-2 protease is the top target for small molecule COVID-19 candidates developed with a coronavirus infection as their original indication, of which only a handful have entered the clinic.
Out of the 281 small molecule candidates in BioCentury’s COVID-19 portal, 22 were developed with SARS-CoV-2, SARS-CoV or another coronavirus as the intended target.
Three of these compounds are in the clinic.
MK-4482, a nucleoside analog from Merck & Co. Inc. (NYSE:MRK), Emory University and Ridgeback Biotherapeutics L.P., inhibits the activity of the viral RNA-dependent RNA polymerase, and is in Phase II testing to treat hospitalized COVID-19 patients.
RBT-9 from Renibus Therapeutics Inc., which inhibits viral replication via an undetermined target, is in Phase II testing for prevention of COVID-19 in high-risk individuals.
PF-07304814 from Pfizer Inc. (NYSE:PFE), which inhibits the protease SARS-CoV-2 3CLpro, is in Phase I testing for hospitalized COVID-19 patients.
At least five other companies have SARS-CoV-2 3CLpro inhibitors in preclinical development: Anivive Lifesciences Inc., Cocrystal Pharma Inc. (NASDAQ:COCP), Insilico Medicine Inc., Pardes Biosciences Inc. and Sosei Group Corp. (Tokyo:4565).
In a conversation with BioCentury, Novartis Institutes for BioMedical Research (NIBR) president Jay Bradner said the similarity between the proteases of SARS-CoV-2 and SARS-CoV represented a missed opportunity; if coronavirus protease research had been sustained in the wake of the SARS epidemic, the world would have had inhibitors ready to deploy against COVID-19 (see “Hard Lessons and Hope in Coronavirus Research”).
Among the seven compounds with undisclosed targets, four are categorized as antivirals, two as immunosuppresants, and one as a metabolic modulator.
Cathepsin L (CTSL)
eIF4E – Eukaryotic translation initiation factor 4E
SARS-CoV-2 3CLpro (SARS-CoV-2 NSP5; SARS-CoV-2 Mpro; SARS-CoV-2 main protease) – SARS-CoV-2 3C-like protease
SARS-CoV-2 AH – SARS-CoV-2 frameshift attenuator hairpin
SARS-CoV-2 S – SARS-CoV-2 spike protein