Structure-guided design of peptide-based tryptase inhibitors.
Improved peptide-based inhibitors of human beta 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.
McGrath
Mary E
ME
Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. mary.mcgrath@gilead.com
Sprengeler
Paul A
PA
Hirschbein
Bernard
B
Somoza
John R
JR
Lehoux
Isabelle
I
Janc
James W
JW
Gjerstad
Erik
E
Graupe
Michael
M
Estiarte
Angeles
A
Venkataramani
Chandru
C
Liu
Yang
Y
Yee
Robb
R
Ho
Joseph D
JD
Green
Michael J
MJ
Lee
Chang-Sun
CS
Liu
Liang
L
Tai
Vincent
V
Spencer
Jeffrey
J
Sperandio
David
D
Katz
Bradley A
BA