Azodicarbonamide (ADA) as an anti-HIV agent that targets the nucleocapsid protein zinc fingers: a clinical candidate

Nucleocapsid p7 (NCp7) proteins participate in multiple phases of HIV-1 replication. The Cys sulfur atoms of the conserved Cys-Xaa(2)-Cys-Xaa(4)-His-Xaa(4)-Cys (CCHC) zinc-binding domains in the NCp7 are susceptible to electrophilic attack by selected 2,2'-dithiobisbenzamide (DIBA) compounds, dithianes, and others functional groups. Such NC inhibitors demonstrated broad antiretroviral activity, were directly virucidal, blocked initiation of reverse transcription, and prevented Gag precursor processing. Drug-resistant isolates were not detected after more than two years in culture with DIBAs. Because of the promising nature of NC inhibitors, we initiated searches for additional chemotypes that inhibit HIV-1 through modification of the zinc finger domains. Azodicarbonamide (ADA, NSC 674447) was discovered as an azoic-based compound that inhibits HIV-1 replication in vitro. We report biochemical and NMR evidence that ADA functions by electrophilical attack on the nucleophilic sulfur atoms of the zinc-coordinating cysteine residues of the CCHC domain, causing ejection of zinc from the array. ADA inhibited a broad range of retrovirusses and was directly virucidal, but did not inhibit HIV-1 binding to target cells or the enzymatic activities of RT, protease or integrase. Vandevelde et al. (AIDS Res. Hum. Retro. 12, 567, 1996) recently reported that ADA, which inhibited HIV-1 infection via an unidentified mechanism, has been introduced to Phase I/II clinical trials in Europe for advanced AIDS. Thus, ADA is the first NC inhibitor to progress to in vivo evaluation, and sets a precedent for this new class of anti-HIV agents as clinical candidates.

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