Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein.

Nat Med. 1997 Mar;3(3):341-5. Unique Identifier : AIDSLINE MED/97208923
Rice WG; Turpin JA; Huang M; Clanton D; Buckheit RW Jr; Covell DG; Wallqvist A; McDonnell NB; DeGuzman RN; Summers MF; Zalkow L; Bader JP; Haugwitz RD; Sausville EA; Laboratory of Antiviral Drug Mechanisms, National Cancer; Institute-Frederick Cancer Research and Development Center, SAIC; Frederick, Maryland 21702, USA.

Abstract: Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.

Keywords: *Antiviral Agents/PHARMACOLOGY *Azo Compounds/PHARMACOLOGY *Capsid/DRUG EFFECTS *Gene Products, gag/DRUG EFFECTS *HIV Infections/VIROLOGY *HIV-1/PHYSIOLOGY *Virus Replication/DRUG EFFECTS
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