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Science 17 November 1995:
Vol. 270. no. 5239, pp. 1194 - 1197
DOI: 10.1126/science.270.5239.1194
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Reports

Inhibitors of HIV Nucleocapsid Protein Zinc Fingers as Candidates for the Treatment of AIDS

William G. Rice (1),  Jeffrey G. Supko,  Louis Malspeis,  Robert W. Buckheit Jr.,  David Clanton,  Ming Bu,  Lisa Graham,  Catherine A. Schaeffer,  Jim A. Turpin,  John Domagala,  Rocco Gogliotti,  John P. Bader,  Susan M. Halliday,  Lori Coren,  Raymond C. Sowder II,  Larry O. Arthur,  Louis E. Henderson

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.


W. G. Rice, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, Laboratory of Antiviral Drug Mechanisms, PRI/DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
J. G. Supko and L. Malspeis, Laboratory of Pharmaceutical Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Frederick, MD 21701-8527, USA.
R. W. Buckheit Jr. and S. M. Halliday, Virology Research Group, Southern Research Institute-Frederick Research Center, Frederick, MD 21701, USA.
D. Clanton, Anti-AIDS Virus Drug Screening Laboratory, PRI/DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
J. Domagala and R. Gogliotti, Chemistry Department, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
J. P. Bader, Antiviral Evaluations Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892, USA.
L. Coren, R. C. Sowder II, L. O. Arthur, L. E. Henderson, AIDS Vaccine Program, PRI/DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
(1) To whom correspondence should be addressed.


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