Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

Abstract

A series of piperidine-based peptidomimetic inhibitors have been synthesized and evaluated their activity against the three serine proteases HGFA, matriptase, and hepsin. All analogs showed nanomolar activity against matriptase and hepsin.

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

“…Rational design of TMPRSS2-selective kbt inhibitors. We have employed X-ray cocrystal structure data in the rational design of optimized HGFA, matriptase, and hepsin inhibitors with increased potency and selectivity (35)(36)(37)(38). Shown in Fig.…”

“…Like TMPRSS2, other TTSPs such as matriptase and hepsin have a canonical serine protease domain residing as the C-terminal domain of the protein that is anchored to the cell membrane by an N-terminal type II signal peptide, thereby presenting their enzymatic activity outside the cell. We have previously reported on the discovery and anticancer properties of peptidomimetic ketothiazole (kt) and kbt inhibitors of HGFA, matriptase, and hepsin ( 35 – 39 ) named synthetic HGF Activation Inhibitors or sHAIs. Since TMPRSS2 has an overlapping endogenous substrate specificity profile with HGF-activating proteases, we postulated that our substrate-based sHAIs would also inhibit TMPRSS2.…”

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

“…28,29 Like TMPRSS2, other TTSPs such as matriptase and hepsin have a canonical serine protease domain residing as the C-terminal domain of the protein that is anchored to the cell membrane by an Nterminal type II signal peptide thereby presenting their enzymatic activity outside the cell. We have previously reported on the discovery and anticancer properties of peptidomimetic ketothiazole (kt) and ketobenzothiazole (kbt) inhibitors of HGFA, matriptase and hepsin [30][31][32][33][34] named synthetic HGF Activation Inhibitors or sHAIs. Since TMPRSS2 has an overlapping endogenous substrate specificity profile with HGF-activating proteases, we postulated that our substrate-based sHAIs would also inhibit TMPRSS2.…”

“…While we previously pursued this chemical series as HGFA, matriptase and hepsin inhibitors 33 , the best series we have developed are small peptide-based molecules like 1, 2 and 3 (Ac-SKLRkbt; Figure 3B) which exhibit low nM to picomolar IC50s. These compounds contain a serine trapping ketobenzothiazole (kbt) warhead [30][31][32]34 which reacts covalently with the protease, but importantly in a reversible manner, unlike Camostat or Nafamostat in which the inhibition is irreversible. Therefore, we pursued the kbt class of inhibitors for lead identification studies towards more potent and selective TMPRSS2 inhibitors.…”

“…We have employed X-ray co-crystal structure data in the rational design of optimized HGFA, matriptase and hepsin inhibitors with increased potency and selectivity [30][31][32][33] .…”