Highly active anti-retroviral therapy can effectively control virus replication in HIV-1 positive individuals. However, problems such as drug resistance and side effects often compromise the effectiveness of anti-HIV- 1 drugs. Therefore, the development of new anti-HIV agents with novel mechanisms of action is needed. In an effort to identify novel anti-HIV-1 agents, we have synthesized potent bi-functional betulinic acid (BA) derivatives that inhibit both HIV-1 entry and maturation by targeting gp120 and gag proteins. Although these small molecules inhibit HIV-1 at low nanomolarity concentrations and have different mechanisms of actions from other anti-HIV-1 drugs, the clinical potential of this class of compounds has not been evaluated. The objective of this project is to synthesize and identify potent bi-functional anti-HIV BA derivatives for further clinical development. This is a step toward our long term goal to develop anti-HIV-1 agents with novel mechanisms of action for AIDS therapy. The central hypothesis of this study is that the dual novel mechanisms of action of the bi-functional BA derivatives will allow the compounds to potently inhibit HIV-1 including strains already resistant to current anti-HIV drugs. In addition, the dual mechanisms of action are likely to slow the emergence of mutants resistant to the bi-functional BA derivatives. We plan to test this hypothesis and accomplish the objective of this study with the following specific aims: 1. To synthesize the bi-functional BA derivatives that are more potent than the current lead compounds. 2. To determine the molecular mechanisms of action and drug resistance profiles of the bi-functional BA derivatives. 3. To determine the efficacy of the bi-functional BA derivatives against HIV-1 primary isolates and bioavailability in small animals. In addition, the effect of the bi-functional BA derivatives on drug resistant viruses and HIV-1 replication in a SCID-hu mouse model will also be determined. The novel mechanisms of action and the ability to inhibit two targets make the bi-functional BA derivatives promising candidates for anti-HIV therapy. Results of the proposed study are expected to provide insights into the clinical potential of this class of compounds for AIDS therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Discovery and Development of Therapeutics Study Section (ADDT)
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Black, Paul L
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Duke University
Schools of Medicine
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