Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer.
The zinc fingers of the HIV-1 nucleocapsid protein, NCp7, are prime targets for antiretroviral therapeutics. Here we show that S-acyl-2-mercaptobenzamide thioester (SAMT) chemotypes inhibit HIV by modifying the NCp7 region of Gag in infected cells, thereby blocking Gag processing and reducing infectivity. The thiol produced by SAMT reaction with NCp7 is acetylated by cellular enzymes to regenerate active SAMTs via a recycling mechanism unique among small-molecule inhibitors of HIV.
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Lisa M
LM
Miller Jenkins
David E
DE
Ott
Ryo
R
Hayashi
Lori V
LV
Coren
Deyun
D
Wang
Qun
Q
Xu
Marco L
ML
Schito
John K
JK
Inman
Daniel H
DH
Appella
Ettore
E
Appella
D000107:Acetylation; D000215:Acylation; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D015750:Genes, gag / Q000235:genetics; D008969:Molecular Sequence Data; D054852:Small Molecule Libraries; D016335:Zinc Fingers / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D001549:Benzamides; C071884:NCP7 protein, Human immunodeficiency virus 1; C554254:S-acyl-2-mercaptobenzamide thioester; D054852:Small Molecule Libraries; D054301:gag Gene Products, Human Immunodeficiency Virus