AZODICARBONAMIDE INHIBITS HIV-1 REPLICATION BY TARGETING THE NUCLEOCAPSID PROTEIN

Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)(2)-C ys-(X)(4)-His-(X)(4)-Cys (CCHC)(1,2). The spacing pattern and metal-ch elating residues (3 Cys, 1 His) of these nucleocapsid CCHC zinc finger s are highly conserved among retroviruses(1,3,4). These CCHC domains a re required during both the early(5,6) and late(7,8) phases of retrovi ral replication, making them attractive targets for antiviral agents. Toward that end, we have identified a number of antiviral chemotypes t hat electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains(9-14). Such nucleocapsid inhibitors were directly virucidal by preventing the initiation of reverse transc ription(15) and blocked formation of infectious virus from cells throu gh modification of CCHC domains within Gag precursors(16). Herein we r eport that azodicarbonamide (ADA) represents a new compound that inhib its HIV-1 and a broad range of retroviruses by targeting the the nucle ocapsid CCHC domains. Vandevelde et al.(17) also recently disclosed th at ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for adva nced AIDS. These studies distinguish ADA as the first known nucleocaps id inhibitor to progress to human trials and provide a lead compound f or drug optimization.