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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Probing Proteinase Active Sites Using Oriented Peptide Mixture Libraries - ADAM-10

Author(s): John L. Krstenansky, Jihong Wang, Gregg R. Chenail, Matthew R. Tiffany, Geoffrey M. Kuesters, Barbara C. Natke and John J. Nestor, Jr.

Volume 1, Issue 1, 2004

Page: [6 - 13] Pages: 8

DOI: 10.2174/1570180043485770


Oriented Peptide Mixture Libraries can provide a full matrix of preferred and disfavored amino acids at each subsite of an optimal substrate for a new proteinase. This approach is rapid and convenient, requiring only two mixture libraries to complete the analysis. In this paper we demonstrate an extension of this type of analysis, using a focused library employing unnatural amino acids to probe the depth of the S1 position in the catalytic site of the alpha secretase ADAM-10. This analysis indicates that ADAM- 10 will accept amino acids with substantial length and hydrophobicity (e.g. 2- naphthylalanine), but suggests that the S1 site has limitations in the apparent “width” of substituents being presented (e.g. 1-naphthylalanine; gamma branching). A highly selective and efficient substrate for ADAM-10, with a selectivity factor of 380,000 M-1 s-1, was derived from the predicted consensus substrate. This detailed analysis provides a starting point for the design of inhibitors of this interesting proteinase.

Keywords: proteinase, proteinase inhibitor, proteinase substrate, adam-10, consensus substrate motif

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