Small-molecule dimerization inhibitors of wild-type and mutant HIV protease: a focused library approach.
We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that an additive increase in inhibitor efficacy was obtained. The good activity of library members against an active-site drug-resistant protease mutant bodes well for dimerization inhibition as a complementary method to targeting the active site.
Shultz
Michael D
MD
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Ham
Young-Wan
YW
Lee
Song-Gil
SG
Davis
David A
DA
Brown
Cara
C
Chmielewski
Jean
J
D001665:Binding Sites; D019281:Dimerization; D024882:Drug Resistance, Viral / Q000235:genetics; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D016333:HIV Protease