Acquired immunodeficiency syndrome (AIDS) is an immunosuppressive disease that results in life-threatening opportunistic infections and malignancies. Emphasis now has been placed on discovery and development of novel agents, including natural products, against viral and host factors involved in HIV transmission and infection, as well as therapeutics for opportunistic disease pathogens. Among these emerging therapies, natural products are receiving increased attention. Phytochemical investigations of the Rheedia brasiliensis'fruit resulted in the isolation and identification of new potentially bioactive benzophenones. The polyprenilated benzophenones have shown anti-microbial, anti-fungal and anti-HIV activity. However, the mechanism(s) of action of benzophenoes against both HIV and opportunistic infections, including Candida, has yet to be determined. The central objective is to identify the targets that mediate the activity of benzophenones on both HIV and the opportunistic microorganism Candida sp. and to identify the natural compounds with the highest therapeutic index. Mentored k99 phase: The mentored phase of the proposal will be carried out under the mentorship of Prof. Daniel Malamud and Prof. Simone Duarte at New York University. The goal of this phase is to evaluate the antiviral activity and toxicity of benzophenones on immortalized cell lines to establish the therapeutic index for both M-tropic and T-tropic strains of HIV-1;
Aim 2) Identify and characterize specific molecular target(s) by which the benzophenones inhibit HIV infection through interaction with viral gp120 or mammalian cell receptors for the virus using circular dichroism, biosensor analysis and Aim 3) Evaluate and characterize the anti-fungal effect of benzophenones against C. albicans biofilms and determine how these agents affect the content and composition of the polysaccharide matrix, using a combination of fluorescence imaging techniques and Scanning Electron Microscopy. These studies will provide the structural data on modification of the biofilm matrix by the benzophenones, e.g. spatial distribution of biofilm matrix and fungi, and linkage composition of the polysaccharides. This training will provide expertise in virology, structure determination, and cell culture techniques. The acquired knowledge will provide the foundation for transition to an independent career. During the independent phase, I will continue my study with natural molecules to identify additional pathways that may contribute to prevent or treat infectious diseases and assess their potential in vivo.
The development of novel agents derived from natural products that have the ability to inhibit both HIV and HIV-associated pathogens will have major impact on the HIV/AIDS epidemic, both in terms of developing new therapeutic agents, and demonstrating the unique activities of natural products with activity directed against multiple pathogens. The successful completion of the proposed studies has the potential to change the current strategies for dealing with both viral and microbial pandemics as well as promoting the value of therapeutic agents derived from natural products.
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