A -- Chemical Optimization and Preclinical Development of HIV-1 Nucleocapsid-p7 Protein-Nucleic Acid Antagonists.

The National Cancer Institute (NCI)-Developmental Therapeutics Program (DTP) - Screening Technologies Branch (STB, in collaboration with the NCI-Retroviral Assembly and Protein Chemistry Laboratories and the AIDS Vaccine Program), have identified several classes of lead compounds which are antagonists of high affinity binding of the HIV-1 nucleocapsid-p7 protein to nucleic acids [e.g. alternating d(TG)n], thereby inhibiting viral replication in HIV-1 infected human CEM SS cells. One such example is the substituted arylstibonic acid, I which exhibits in vitro activity in a virus disassembly assay, disrupting viral particles formed from in vitro-assembled gag particles. Compound I also exhibits excellent correlation between virus particle disassembly activity and NC-p7 and ^p6- d(TG)4 complex disruption and protects CEM SS cells from cytopathic effects of the HIV-1 virus in whole cell/live virus assays. The NCI-DTP-STB now seeks a Cooperative Research and Development Agreement (CRADA) collaborator to participate in the preclinical anti-HIV viral development of compound I which possesses a distinct mechanism of action, is relatively non-toxic and has the potential for use in combination with antiviral drugs acting through differing mechanisms of action. Compound I: see http://ttb.nci.nih.gov/cradaopp39.html for structure Potential Areas of Application: Antiviral (HIV) agent Main advantages of the technology: Compound I: a) inhibits viral replication, transmission and promotes viral inactivation; b) is relatively non-toxic; c) is active in whole cell/live virus assays; and, d) has potential for use in combination antiviral therapy. Current State of Development: Inhibition binding studies were performed with a fluorescence anisotropy assay. Using surface plasmon resonance technology, a subset of compounds correlated well with the anisotropy results. In vitro evaluation indicated a comparable pattern of antiviral activity. Further R&D Required: Development would include optimizing lead compound(s) for activity, potency, formulation, stability, metabolism, toxicity, absorption/distribution etc. Biological testing would be carried out by the NCI-STB, the organizational component of NCI-DTP responsible for the development and operation of in vitro drug screening tools and detailed development and investigation of novel therapeutic agents for the treatment of AIDS, opportunistic infections, and AIDS-related malignancies. Patent Status and Pertinent References: U.S. Patent Application filed on October 8, 2002. Contact Information: Bjarne Gabrielsen, Ph.D., Senior Advisor, Drug Discovery and Development, Technology Transfer Branch, NCI-Frederick, Fairview Center, Suite 502, 1003 - W. 7th Street, Frederick, MD 21701-8512. Phone: (301) 846-5465; Fax: (301) 846-6820; email: [email protected] Last updated 05/12/04