DESCRIPTION (provided by applicant): The AIDS epidemic caused by the HIV retrovirus is one of the leading threats posed to global health by an infectious agent. Limited availability of expensive anti-HIV drugs in the developing world, as well as emergence of drug-resistant HIV strains, highlight the continued need for identification and development of novel HIV prevention and treatment methods, drug targets and drugs. Disruption of viral assembly is a promising antiviral treatment strategy, but the progress in this direction has been slow due to the multivalent nature of the viral assembly process and due to the lack of efficient assembly assays suitable for drug screening and lead optimization. Our recent results revealed an evolutionary relationship between the zinc- finger associated SCAN domain and the retroviral capsid C-terminal domain (CA-CTD), and suggested a mechanism for capsid-mediated Gag oligomerization in retroviral assembly. The main hypothesis of this proposal is that the domain-swapped dimer observed in the SCAN structure represents a critical conformation of CA-CTD adopted during viral assembly. The functional clues provided by the SCAN structure will be used to identify critical molecular determinants of capsid dimerization, and to investigate the proposed role of the SCAN-like domain-swapped CA-CTD dimer (Aim 1). Sensitive and robust assays of CA-CTD dimerization will be developed and used for identification of capsid dimerization inhibitors by high throughput screening and rational design. The anti-HIV potential of the identified compounds will be evaluated (Aim 2).
|Effective start/end date||3/1/07 → 2/28/10|
- National Institutes of Health: $227,416.00
- National Institutes of Health: $247,357.00
- Immunology and Microbiology(all)