ABSTRACT
Potent inhibitors of human cysteine proteases of the papain family have been made and assayed versus a number of relevant family members. We describe the synthesis of peptide alpha-ketoheterocyclic inhibitors that occupy binding subsites S1'-S3 of the cysteine protease substrate recognition cleft and that form a reversible covalent bond with the Cys 25 nucleophile. X-ray crystal structures of cathepsin K both unbound and complexed with inhibitors provide detailed information on protease/inhibitor interactions and suggestions for the design of tight-binding, selective molecules.
Subject(s)
Benzoxazoles/chemistry , Cathepsins/antagonists & inhibitors , Cathepsins/chemistry , Enzyme Inhibitors/chemistry , Oligopeptides/chemistry , Animals , Aspartic Acid/genetics , Binding Sites/genetics , Cathepsin K , Cathepsins/genetics , Crystallography, X-Ray , Humans , Kinetics , Models, Molecular , Rabbits , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Tyrosine/genetics , Valine/geneticsABSTRACT
Reaction alpha- and beta-xanthates 2 and 3 of sialic acid with glycosyl acceptors 5-8 in the presence phenylsulfenyl triflate (PST) as a promotor in a 2:1 mixture of CH(3)CN/CH(2)Cl(2) at low temperature affords alpha-sialosides in good yield and stereoselectivity. PST is prepared in situ by reacting benzenesulfenyl chloride with silver triflate. Less reactive acceptors 5 and 6 give a higher alpha/beta ratio than more reactive allylic alcohol 7 and primary alcohol 8; alpha-stereoselectivity is increased in a dilute solution. A possible mechanism of the reaction that involves intermediate alpha- and beta-nitrilium cations 16 and 17 is discussed.
