Benzophenones: Novel natural agents which inhibits HIV and Candida

描述(申请人提供)：获得性免疫缺陷综合症(艾滋病)是一种免疫抑制疾病，会导致危及生命的机会性感染和恶性肿瘤。现在的重点是发现和开发新的药物，包括天然产品，以对抗艾滋病毒传播和感染中涉及的病毒和宿主因素，以及治疗机会性疾病病原体的方法。在这些新兴疗法中，天然产品正受到越来越多的关注。通过对巴西大黄果实的植物化学研究，分离和鉴定了具有潜在生物活性的新的二苯甲酮类化合物。聚丙基二苯甲酮类化合物具有抗微生物、抗真菌和抗HIV活性。然而，二苯甲酚对艾滋病毒和包括念珠菌在内的机会性感染的作用机制(S)尚未确定。中心目标是确定介导二苯甲酮对艾滋病毒和机会微生物假丝酵母菌活性的靶标。并鉴定出治疗指数最高的天然化合物。指导K99阶段：计划的指导阶段将在纽约大学Daniel Malamud教授和Simone Duarte教授的指导下进行。此阶段的目标是评估二苯甲酮类化合物对永生化细胞株的抗病毒活性和毒性，以确立对M嗜性和T嗜性艾滋病毒1型毒株的治疗指数；目的2)利用圆二色谱、生物传感器分析和目标3)结合荧光成像技术和扫描电子显微镜，确定和表征二苯甲酮类化合物通过与病毒gp120或哺乳动物细胞受体相互作用抑制艾滋病毒感染的特异性分子靶点(S)；目的3)评估和表征二苯甲酮类化合物对白色念珠菌生物被膜的抗真菌作用，并确定这些制剂如何影响多糖基质的含量和组成。这些研究将提供二苯甲酮类化合物修饰生物膜基质的结构数据，如生物膜基质和真菌的空间分布，以及多糖的连接组成。这项培训将提供病毒学、结构测定和细胞培养技术方面的专业知识。获得的知识将为过渡到独立的职业生涯奠定基础。在独立阶段，我将继续我对自然分子的研究，以确定可能有助于预防或治疗传染病的其他途径，并评估它们在体内的潜力。 与公共卫生相关：从能够抑制艾滋病毒和艾滋病毒相关病原体的天然产品中提取的新型制剂的开发将对艾滋病毒/艾滋病疫情产生重大影响，这既包括开发新的治疗剂，也表明天然产品具有针对多种病原体的独特活性。拟议研究的成功完成有可能改变目前应对病毒和微生物流行病的战略，并促进从天然产品中提取的治疗剂的价值。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.