AEGiS-11IAC: Dithiane-type inhibitors of retroviral zinc fingers as leads for anti-HIV-1 drug development.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Dithiane-type inhibitors of retroviral zinc fingers as leads for anti-HIV-1 drug development.

Int Conf AIDS 1996 Jul 7-12; 11:212 (abstract no. Th.A.150)
Rice WG, Turpin J, Arthur L, Henderson L, Bader J, Narayanan V, Buckheit R Jr; NCI-FCRDC, Frederick, MD. Fax: 301-846-6846. E-mail: rice@dtpax2.ncifcrf.gov.

ISSUE: Dithiane-type inhibitors of retroviral zinc fingers inhibit replication of HIV-1 and other retroviruses in cell culture even after the compounds are treated with glutathione.

PROJECT: Nucleocapsid proteins (NC) of all lentiviruses and oncoviruses contain highly conserved 14-residue zinc finger motifs having 3 cysteines and 1 histidine arranged in the Cys-X2-Cys-X4-His-X4-Cys (CCHC) sequence. These fingers are essential both for genomic RNA packaging and for early phase infectious events. We have shown that various electrophilic reagents can chemically interact with the CCHC fingers and inactivate HIV-1. Recently we reported that certain disulfide-substitute benzamides (DIBAs) selectively attack the fingers, inactivate HIV-1 and other retroviruses, block acute and chronic infections, and that drug-resistant virus isolates have not emerged (Rice et al., Science vol. 270, 1995). Because in vivo reduction by glutathione might dissociate and effectively inactivate the bis-disulfide DIBA compounds, we searched the NCI chemical repository for disulfide-based compounds in which the sulfur atoms were tethered in a ring structure that would prevent dissociation of the molecule.

RESULTS: Over 250 dithiane compounds were identified having either a five or six-membered ring structure. The lead compound, 4,5-cis-dihydroxy (dithiane-1, 1-dioxide), demonstrated broad anti-retroviral activity, ranging from field isolates and drug-resistant strains of HIV-1 to HIV-2 and SIV. Through a specific action on the CCHC zinc fingers the compound inactivated cell-free HIV-1 virions and blocked production of infectious virus from chronically infected cells. In addition, compound treated with glutathione continued to exert an antiviral effect.

LESSONS LEARNED: Because of the potential for regeneration of the active form of the reagent, the dithianes tender an advantage over the DIBA-type compounds. Dithianes that are reactive with retroviral zinc fingers offer a novel avenue for development of therapeutics for the treatment of HIV-1 infection.

Keywords: AEGIS, HIV-1, Zinc Fingers, Gene Products, gag, Virus Replication, Anti-HIV Agents, HIV Infections, HIV Core Protein p24, HIV Protease, Capsid, HIV-2, Disulfides, SIV, Benzamides, Nucleocapsid Proteins, Viral Core Proteins, Commonwealth of Independent States, virology, ICA11

960707
ThA150