The chemokine receptor CCR5 is one of the essential co-receptors for the HIV virus entry to host cells. The application of CCR5 antagonist in blocking the virus entry will provide a novel anti-HIV therapeutic pathway. The long-term goal of our project is to develop potential antagonist(s) of chemokine receptor CCR5 as novel anti-HIV agents. Anibamine is the first and only natural product that has been reported to have inhibition affinity to CCR5 at 1 micromole. The specific hypothesis of this exploratory/developmental project is that an antagonist of CCR5 with structural character of anibamine may have therapeutic potency as anti-HIV agents. We base that hypothesis on the following facts: First, this natural product provides a novel structural skeleton as CCR5 antagonist compared with all other known high-throughput screening observations. Second, the binding pocket study of anibamine in CCR5 homology model has shown some common features that may be shared by other reported CCR5 antagonists. Therefore, the chemical synthesis of anibamine and its analogs acting as CCR5 antagonist may lead to a brand new type of chemotherapeutic agent for the HIV/AIDS treatment. Based on these observations, the focus of this proposal is the synthesis of CCR5 non-peptide antagonists carrying structural features of anibamine. The specific aims are to (1) design and synthesize novel compounds as anibamine derivatives acting as novel CCR5 antagonists and (2) to evaluate the ligands synthesized for anti-HIV activity to develop the next generation lead compound. So far we have accomplished the total synthesis of anibamine by the exploration of multiple synthetic routes. We also have applied the homology model of CCR5 that we built to study the binding locus for anibamine and other known antagonists. A series of new ligands have been designed and their synthetic routes have been proposed based on our total synthesis results. This exploratory/developmental project will focus on the development of novel lead compound with the structural character of anibamine as the new anti-HIV agents. PUBLIC HEALTH RELEVANCE: The long-term goal of our project is to develop potential antagonist(s) of chemokine receptor CCR5 as anti-HIV/AIDS agents. This exploratory/developmental project will focus on the development of novel lead compound with the structural character of anibamine, the first and only natural product as CCR5 antagonist, as new anti-HIV agents. We believe it is urgent to pursue this study in order to identify new lead compounds as novel CCR5 antagonist, and to exploit the antiviral activity of these ligands.