A collaborative investigation has been initiated this past year to find effective chemical inhibitors of the human immunodeficiency virus (HIV) by targeting highly conserved structures within the virus particle, namely, the zinc fingers of the nucleocapsid protein p7 (NCp7). These zinc protein structures control the expression of a segment of the viral genomic RNA involved in replication and assembly of the virus. Relative intolerance to mutations affecting NCp7 should render drugs targeting this region unlikely to induce drug-resistant strains of HIV. The work is being shared between this Section and the Laboratory of Cell Biology (NCI), the Laboratory of Antiviral Drug Mechanisms and Laboratory of Mathematical Biology (NCI, Frederick, MD). In drug design we are departing from known NCp7 inhibitors of the disulfide dibenzamide type in order to more effectively destroy the zinc finger structures, likewise, through formation of covalent linkages with their constituent cysteine sulfhydryl groups.
The aim i s to develop a relatively nontoxic, inexpensive antiviral drug that can be used to treat infections with all strains of HIV-1 and HIV-2. Active lead compounds have been identified through a variety of in vitro tests that assess antiviral activity, toxicity, target specificity and mechanism of action. One compound is currently being considered for testing in an animal (mouse) model of human HIV infection. This laboratory has been mainly responsible for directing the design and synthesis of trial compounds and for assisting in their synthesis.
