The work done in this project has been an integral part of a team effort with NCI and NIAID laboratories to develop new inhibitors of HIV that target the highly conserved nucleocapsid protein (NCp7). The Bioorganic Chemistry Section has the responsibility to design the actual drug candidates and to direct and participate in their synthesis. As reported last year, we began exploring a number of variants of dithiobis(benzamides), a class of compounds previously shown by our group and others to selectively inactivate NCp7 through covalent modification of its zinc finger cysteines. In the course of this work, we synthesized other chemotypes and discovered that certain thioesters showed considerable promise as antiviral agents as tested by in vitro assays for zinc ejection from recombinant NCp7, HIV antiviral potency (XTT test), and cellular toxicity. Some of these compounds, because of their low toxicity, exhibited very good therapeutic indices (low toxicity coupled with good potency). We have synthesized and screened a panel of the thioesters, exploring various aspects of structure in relation to function. In particular, we identified a subclass of thioesters that bear a pyridinium cationic group, the pyridinioalkanoyl thioesters. Their low molecular weight and stability toward glutathione highlight potential advantages over the dithiobis(benzamides) and derivative benzisothiazolones, especially in regard to bioavailability and in vivo efficacy. A worldwide patent (PCT) was filed during the past year covering the 2-mercaptobenzamide thioester chemotype as anti-HIV candidates active in inhibiting the nucleocapsid zinc finger structures. The patent covers other possible applications, including the inactivation of other retroviruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000786-04
Application #
6431681
Study Section
(LI)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Eller, Nancy; Golding, Hana; Inoue, Satoshi et al. (2004) Systemic and mucosal immunity in rhesus macaques immunized with HIV-1 peptide and gp120 conjugated to Brucella abortus. J Med Primatol 33:167-74
Schito, Marco L; Goel, Atul; Song, Yongsheng et al. (2003) In vivo antiviral activity of novel human immunodeficiency virus type 1 nucleocapsid p7 zinc finger inhibitors in a transgenic murine model. AIDS Res Hum Retroviruses 19:91-101
Mongini, Patricia K A; Jackson, Anna E; Tolani, Sonia et al. (2003) Role of complement-binding CD21/CD19/CD81 in enhancing human B cell protection from Fas-mediated apoptosis. J Immunol 171:5244-54
Song, Yongsheng; Goel, Atul; Basrur, Venkatesha et al. (2002) Synthesis and biological properties of amino acid amide ligand-based pyridinioalkanoyl thioesters as anti-HIV agents. Bioorg Med Chem 10:1263-73
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Basrur, V; Song, Y; Mazur, S J et al. (2000) Inactivation of HIV-1 nucleocapsid protein P7 by pyridinioalkanoyl thioesters. Characterization of reaction products and proposed mechanism of action. J Biol Chem 275:14890-7