Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS.
Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.
Rice
W G
WG
Laboratory of Antiviral Drug Mechanisms, PRI/DynCorp., National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702, USA.
Supko
J G
JG
Malspeis
L
L
Buckheit
R W
RW
Clanton
D
D
Bu
M
M
Graham
L
L
Schaeffer
C A
CA
Turpin
J A
JA
Domagala
J
J
Gogliotti
R
R
Bader
J P
JP
Halliday
S M
SM
Coren
L
L
Sowder
R C
RC
Arthur
L O
LO
Henderson
L E
LE
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D036022:Capsid Proteins; D002460:Cell Line; D004220:Disulfides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D015683:Gene Products, gag / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D014764:Viral Proteins; D016335:Zinc Fingers / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D001549:Benzamides; D036022:Capsid Proteins; D004220:Disulfides; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus