Arginine-based structures are specific inhibitors of cathepsin C. Application of peptide combinatorial libraries.
Novel synthetic peptide inhibitors of lysosomal cysteine proteinase cathepsin C have been designed through the use of soluble peptide combinatorial libraries. The uncovered structural inhibitory module consists of the N-terminal cluster of L-arginine residues. Its modification with D-amino acids or arginine derivatives did not increase the inhibition strength. Inhibitory potency of oligoarginines improves with the elongation of peptide chain reaching a maximum for octa-L-arginine. The oligoarginines specifically interact with the cathepsin C active site as shown by competitive-type inhibition kinetics (Ki approximately 10-5 M) and intrinsic fluorescence measurements. The inhibitory interaction of oligoarginines is established through the specific spatial contact of a net of guanidino groups in the arginine side-chains, as indicated by comparison with inhibitory action of low molecular mass guanidine derivatives (Ki approximately 10-3 M). Nonarginine polyionic compounds cannot mimic the inhibitory effect of oligoarginines. The arginine-based peptide inhibitors were selective towards cathepsin C among other cysteine proteinases tested.
Horn
M
M
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Praha, Czech Republic. horn@marilyn.uochb.cas.cz
Pavlík
M
M
Dolecková
L
L
Baudys
M
M
Mares
M
M
D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D002417:Cattle; D020650:Combinatorial Chemistry Techniques; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D010455:Peptides / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; C015462:polyarginine; D001120:Arginine; D020789:Cathepsin C