Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine.
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
Avila Therapeutics, Inc., Waltham, Massachusetts, USA.
Margit
M
Hagel
Deqiang
D
Niu
Thia
T
St Martin
Michael P
MP
Sheets
Lixin
L
Qiao
Hugues
H
Bernard
Russell M
RM
Karp
Zhendong
Z
Zhu
Matthew T
MT
Labenski
Prasoon
P
Chaturvedi
Mariana
M
Nacht
William F
WF
Westlin
Russell C
RC
Petter
Juswinder
J
Singh
D055162:Biocatalysis; D001671:Biochemistry / Q000379:methods; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014773:Virology / Q000379:methods
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C486464:telaprevir; D003545:Cysteine