Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases.
We describe here the identification of non-peptidic vinylsulfones that inhibit parasite cysteine proteases in vitro and inhibit the growth of Trypanosoma brucei brucei parasites in culture. A high resolution (1.75 A) co-crystal structure of 8a bound to cruzain reveals how the non-peptidic P2/P3 moiety in such analogs bind the S2 and S3 subsites of the protease, effectively recapitulating important binding interactions present in more traditional peptide-based protease inhibitors and natural substrates.
Bryant
Clifford
C
Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA.
Kerr
Iain D
ID
Debnath
Moumita
M
Ang
Kenny K H
KK
Ratnam
Joseline
J
Ferreira
Rafaela S
RS
Jaishankar
Priyadarshini
P
Zhao
DongMei
D
Arkin
Michelle R
MR
McKerrow
James H
JH
Brinen
Linda S
LS
Renslo
Adam R
AR
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057056:Cysteine Proteases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects
D000577:Amides; D011480:Protease Inhibitors; C546159:SMDC 256047; D013450:Sulfones; D014344:Trypanocidal Agents; D057056:Cysteine Proteases