Nucleocapsid (NC) proteins of retroviruses contain sequences of 14 amino acids with 4 invariant residues, Cys(X)2Cys(X)4His(X)4Cys(CCHC), that chelate zinc through histidine imidazole and cysteine thiolates(K(d)less than 10(3)). The CCHC motif is one of the most highly conserved features in retroviruses and is necessary to package genomic RNA into the virus. Mutants with altered zinc-chelating residues (CCCC and CCHH) package genomic RNA but are still noninfectious; thus the CCHC motif is essential for early infection event(s). This apparent immutability of the CCHC finger makes this structure an ideal drug target. We find that the conserved cysteine thiolates (S*) in the finger can be destroyed by electrophilic reagents and retrovirus particles are inactivated by exposure to the reagents. We have developed a screening pathway which begins with identification of lead compounds based on structure and functional groups and extends to demonstration of activity on purified NC protein, reaction with zinc fingers in the intact virus, anti-viral activity in tissue culture, anti-viral activity in a SFFV/murine model and anti-viral activity in SIV-infected macaques. Results of this drug evaluation screen will be discussed.

Antiviral Agents/CHEMICAL SYNTHESIS/*PHARMACOLOGY Capsid/METABOLISM Chelating Agents HIV-1/*DRUG EFFECTS/GENETICS/METABOLISM Human Structure-Activity Relationship *Zinc Fingers ABSTRACT

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