Benzophenones: Novel natural agents which inhibits HIV and Candida

描述（由申请人提供）：获得性免疫缺陷综合征（AIDS）是一种免疫抑制性疾病，可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，以对抗参与艾滋病毒传播和感染的病毒和宿主因素，以及机会性疾病病原体的治疗方法。在这些新兴疗法中，天然产品受到越来越多的关注。巴西大黄果实的植物化学研究导致了新的潜在生物活性的二苯甲酮的分离和鉴定。聚戊二酸二苯甲酮已显示出抗微生物、抗真菌和抗HIV活性。然而，二苯甲酮对艾滋病毒和机会性感染（包括念珠菌）的作用机制尚未确定。中心目标是确定介导二苯甲酮对HIV和机会性微生物念珠菌属的活性的靶点，并确定具有最高治疗指数的天然化合物。K99阶段：该建议的辅导阶段将在纽约大学的丹尼尔·马拉默德教授和西蒙娜·杜阿尔特教授的指导下进行。这一阶段的目标是评价二苯甲酮对永生化细胞系的抗病毒活性和毒性，以确定HIV-1嗜M性和嗜T性毒株的治疗指数;目的2）使用圆二色性鉴定和表征二苯甲酮通过与病毒gp 120或病毒的哺乳动物细胞受体相互作用来抑制HIV感染的特异性分子靶标，生物传感器分析和目的3）评价和表征二苯甲酮对C.白色念珠菌生物膜，并确定这些代理商如何影响的内容和组成的多糖矩阵，使用荧光成像技术和扫描电子显微镜的组合。这些研究将提供二苯甲酮修饰生物膜基质的结构数据，例如生物膜基质和真菌的空间分布，以及多糖的连接组成。该培训将提供病毒学、结构测定和细胞培养技术方面的专业知识。所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，我将继续研究天然分子，以确定可能有助于预防或治疗传染病的其他途径，并评估其在体内的潜力。 公共卫生相关性：开发具有抑制HIV和HIV相关病原体的能力的衍生自天然产物的新型药剂将对HIV/AIDS流行病产生重大影响，无论是在开发新的治疗剂方面，还是在展示具有针对多种病原体的活性的天然产物的独特活性方面。拟议研究的成功完成有可能改变目前应对病毒和微生物大流行病的战略，并提高天然产品治疗剂的价值。

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.