Fig. 1: Ketobenzothiazole-based peptidomimetics are potent TMPRSS2 inhibitors.
From: A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
a, Peptidomimetic compounds used in this study along with their respective sequences. The structures of N-terminal caps, the ketobenzothiazole warhead and the alcohol ketobenzothiazole are shown on the right. (H)Arg, desamino arginine; kbt, ketobenzothiazol. b, Vero E6 cells were transfected with an empty vector (mock), wild-type TMPRSS2 or the inactive mutant TMPRSS2(S441A) for 24 h. The indicated compounds (10 nM) were added concomitantly with a fluorogenic substrate on cells for an additional 24 h before fluorescence reading. Relative TMPRSS2 activity was measured using the mock-subtracted fluorescence and is reported as the percentage of residual activity relative to the vehicle-treated cells (0.01% DMSO). Data are presented as mean ± s.d. (n = 3 independent experiments). c, Dose–response curves were generated for the indicated compounds using the assay described in b, and IC50 values were determined using nonlinear regression analysis. Representative IC50 curves are shown, with the mean value of independent experiments (n = 3 for N-0130, N-0386 and N-0385(OH); n = 4 for Cm and N-0385; n = 5 for N-0438). d, Specificity of selected compounds toward other serine proteases. Data are the mean of log(Ki); n = 3 independent experiments (except cathepsin L versus N-0385, n = 4) and are shown as a heat map. e, Main image, docking of N-0385 (green; warhead in purple) in the binding pocket of TMPRSS2 (homology model). Residues of the catalytic triad are shown in cyan. Inset, interaction of N-0385 with TMPRSS2 residues. N-0385 forms a covalent bond with the catalytic triad residue Ser441.
