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Article

Structure-Guided Design of Peptide-Based Tryptase Inhibitors

Supporting Info

Mary E. McGrath,* Paul A. Sprengeler, Bernard Hirschbein, John R. Somoza, Isabelle Lehoux, James W. Janc, Erik Gjerstad, Michael Graupe, Angeles Estiarte, Chandru Venkataramani, Yang Liu, Robb Yee, Joseph D. Ho, Michael J. Green, Chang-Sun Lee, Liang Liu, Vincent Tai, Jeffrey Spencer, David Sperandio, and Bradley A. Katz

Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080

Biochemistry, 2006, 45 (19), pp 5964–5973

DOI: 10.1021/bi060173m

Publication Date (Web): April 21, 2006

To whom correspondence should be addressed. Current address: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404. Telephone: (650) 522-1697. Fax: (650) 522-5899. E-mail: mary.mcgrath@gilead.com.

Abstract

Improved peptide-based inhibitors of human β tryptase were discovered using information gleaned from tripeptide library screening and structure-guided design methods, including fragment screening. Our efforts sought to improve this class of inhibitors by replacing the traditional Lys or Arg P1 element. The optimized compounds display low nanomolar potency against the mast cell target and several hundred-fold selectivity with respect to serine protease off targets. Thus, replacement of Lys/Arg at P1 in a peptide-like scaffold does not need to be accompanied by a loss in target affinity.

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