Structure-Guided Design of Peptide-Based Tryptase Inhibitors
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- 作者：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 ; Jos
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：May 16, 2006
- 年：2006
- 卷：45
- 期：19
- 页码：5964 - 5973
- 全文大小：775K
- 年卷期：v.45,no.19(May 16, 2006)
- ISSN：1520-4995
文摘
Improved peptide-based inhibitors of human 
tryptase were discovered using informationgleaned 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.
tryptase were discovered using informationgleaned 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.