Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Benzamides / chemistry
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Benzamides / pharmacokinetics
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Benzamides / pharmacology*
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Biological Availability
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Capsid / chemistry
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Capsid / metabolism*
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Capsid Proteins*
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Cell Line
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Disulfides / chemistry
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Disulfides / pharmacokinetics
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Disulfides / pharmacology*
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Drug Resistance, Microbial
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Drug Synergism
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Gene Products, gag / antagonists & inhibitors*
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Gene Products, gag / chemistry
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HIV-1 / drug effects*
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HIV-1 / physiology
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Humans
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Male
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Mice
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Molecular Sequence Data
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Viral Proteins*
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Zinc Fingers / drug effects*
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gag Gene Products, Human Immunodeficiency Virus
Substances
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Antiviral Agents
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Benzamides
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Capsid Proteins
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Disulfides
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Gene Products, gag
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NCP7 protein, Human immunodeficiency virus 1
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Viral Proteins
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gag Gene Products, Human Immunodeficiency Virus