Evaluation of selected chemotypes in coupled cellular and molecular target-based screens identifies novel HIV-1 zinc finger inhibitors.
Conservation of the Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys retroviral zinc finger sequences and their absolute requirement in both the early and late phases of retroviral replication make these chemically reactive structures prime antiviral targets. We recently reported that select 2,2'-dithiobisbenzamides (DIBAs) chemically modify the zinc finger Cys residues, resulting in release of zinc from the fingers and inhibition of HIV replication. In the current study we surveyed 21 categories of disulfide-based compounds from the chemical repository of the National Cancer Institute for their capacity to act as retroviral zinc finger inhibitors. Aromatic disulfides that exerted anti-HIV activity tended to cluster in the substituted aminobenzene, benzoate, and benzenesulfonamide disulfide subclasses. Only one thiuram derivative exerted moderate anti-HIV activity, while a number of nonaromatic thiosulfones and miscellaneous disulfide congeners were moderately antiviral. Two compounds (NSC 20625 and NSC 4493) demonstrated anti-cultures. The two compounds chemically modified the p7NC zinc fingers in two separate in vitro assays, and interatomic surface molecular modeling docked the compounds efficiently but differentially into the zinc finger domains. The combined efforts of rational drug selection, cell-based screening, and molecular target-based screening led to the identification of zinc finger inhibitors that can now be optimized by medicinal chemistry for the development of biopharmaceutically useful anti-HIV agents.
Rice
W G
WG
Laboratory of Antiviral Drug Mechanisms, National Cancer Institute-Frederick Cancer Research and Development Center, SAIC Frederick, Maryland 21702, USA. rice@dtpax2.ncifcrf.gov
Turpin
J A
JA
Schaeffer
C A
CA
Graham
L
L
Clanton
D
D
Buckheit
R W
RW
Zaharevitz
D
D
Summers
M F
MF
Wallqvist
A
A
Covell
D G
DG
D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000821:virology; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D016335:Zinc Fingers
D019380:Anti-HIV Agents; D004220:Disulfides; D006146:Guanidines; D006834:Hydrazines; C101602:NSC 20625; C101601:NSC 4493; D012333:RNA, Messenger