Peptide-based SARS-CoV-2 3CLpro inhibitor identified for COVID-19
DISEASE CATEGORY: Infectious disease
A peptide-based inhibitor of the protease SARS-CoV-2 3CLpro could treat COVID-19. Synthesis and screening of a combinatorial library of fluorogenic substrates with glutamine in the P1 position, and varied natural and non-natural amino acids at two other positions, to identify the best substrates for SARS-CoV-2 3CLpro yielded an 11-residue peptide with leucine and α-aminobutyric acid at the varied positions. The peptide was then converted from a substrate to an inhibitor by combining it with a vinyl sulfone that acts as an irreversible reactive group. In infected human liver cells, the peptide-based inhibitor reduced cell death with an EC50 of 3.7 uM. Additionally, a probe linking a dye to the peptide-based inhibitor was able to detect SARS-CoV-2 3CLpro in seven patients positive for SARS-CoV-2 RNA, and not in four RNA-negative healthy individuals.
Pfizer Inc. (NYSE:PFE) has PF-07304814, a solubilizing IV pro-drug designed to deliver PF-00835231 to inhibit SARS-CoV-2 3CLpro activity, in Phase I testing. At least eight other groups have SARS-CoV-2 3CLpro inhibitors in preclinical development.
TARGET/MARKER/PATHWAY: SARS-CoV-2 3C-like protease (SARS-CoV-2 3CLpro; SARS-CoV-2 NSP5; SARS-CoV-2 Mpro; SARS-CoV-2 main protease)
EXPERIMENTAL SYSTEM: In vitro; cell culture
LICENSING STATUS: Patent application filed; licensing status unavailable
PUBLICATION DETAILS: Rut, W. et al. Nat. Chem. Biol.; published online Oct. 22, 2020
CONTACT: Wioletta Rut, Wroclaw University of Science and Technology, Wroclaw, Poland
CONTACT: Marcin Drag, same affiliation as above