Aminoethyl benzenesulfonyl fluoride and its hexapeptide (Ac‐VFRSLK) conjugate are both in vitro inhibitors of subtilisin kexin isozyme‐1

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Abstract
Using a number of intramolecularly quenched fluorogenic (IQF) substrates encompassing the subtilisin kexin isozyme‐1 (SKI‐1)‐mediated cleavage sites of various viral glycoproteins, it is revealed that 4‐[2‐minothyl enzene] ulfonylluoride (AEBSF) can inhibit the proteolytic activity of SKI‐1 mostly in a competitive manner. The measured IC50 values range from 200 to 800 nM depending on the nature of the substrate used. This is the first in vitro demonstration of a non‐peptide inhibitor of SKI‐1. In an effort to enhance the selectivity and potency of SKI‐1 inhibition, a hexapeptidyl derivative containing SKI‐1 consensus sequence, Ac‐Val‐Phe‐Arg‐Ser‐Leu‐Lys‐AEBSF, was prepared. The peptide sequence was derived from the primary auto‐activation site of prodomain of SKI‐1 itself terminating at Leu‐Lys138 and contains the crucial P4‐basic and P2 alkyl side chain containing hydrophobic amino acids. Like AEBSF, the hexapeptidyl‐AEBSF analog blocked SKI‐1 cleavages of all IQF‐substrates tested but with enhanced efficiency.