Exploring Novel Targeting Strategies for AIDS Protozoal Pathogens

探索艾滋病原虫病原体的新靶向策略

• 批准号: 8384879
• 负责人: Karen S. Anderson
• 金额: $ 38.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384879
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Adverse effects; Affect; Amino Acids; Antineoplastic Agents; Antiparasitic Agents; Antiviral Therapy; Biochemical; Carbon; Catalysis; Cellular biology; Cessation of life; Combined Modality Therapy; Computational Biology; Coupled; Cryptosporidium; DNA biosynthesis; Dihydrofolate Reductase; Enzyme Inhibition; Enzymes; Evaluation; Fluorouracil; Goals; Growth; HIV Infections; HIV-1; Homology Modeling; Human; Immunocompromised Host; Individual; Infection; Kinetics; Laboratories; Lead; Left; Methodology; Methotrexate; Molecular; Nature; Opportunistic Infections; Parasites; Parasitic infection; Patients; Pharmaceutical Preparations; Protozoa; Reaction; Research; Resistance development; Site; Site-Directed Mutagenesis; Structure; Therapeutic; Thymidylate Synthase; Toxic effect; Toxoplasma; Virus; X-Ray Crystallography; antiretroviral therapy; experience; inhibitor/antagonist; interdisciplinary approach; multidisciplinary; novel; novel therapeutic intervention; pathogen; polypeptide; public health relevance; structural biology; synthetic biology; thymidylate synthase-dihydrofolate reductase

DESCRIPTION (provided by applicant): In the last decade, major strides have been made in antiviral therapies for treatment of AIDS due to HIV infection. Currently, opportunistic infections are the primary cause of suffering and death in individuals with AIDS. Many of these infections are produced by parasites that rarely affect individuals who are not immunocompromised. Unfortunately, successful combination therapies against the HIV-1 virus still leave most patients susceptible to opportunistic parasitic infections. There are few drugs available to treat these parasitic infections. The drugs that are available suffer from a lack of selectivity, resulting in host toxicity, untoward side effects, and ineffectiveness due to development of resistance. Thus there is a need to identify novel targeting strategies that may ultimately lead to therapeutics that are more selective and less toxic. This proposal outlines mechanistic and structural studies that focus on unique bifunctional enzymes present only in parasites that may serve as a potential target for the discovery of novel anti-parasitic drugs for treatment of opportunistic infections in AIDS patients. The central theme of this proposal is that an integrated mechanistic, structural and computational evaluation of the parasitic bifunctional TS-DHFR enzyme at a molecular level will help to identify novel targeting strategies for these unique bifunctional enzymes and provide the necessary proof-of-concept to establish non-active site inhibitors as an effective and novel therapeutic approach. A long-term goal of the proposed research is to take advantage of the unique differences between parasitic and human enzymes and develop novel antiparasitic drugs for the treatment of opportunistic parasitic infections. To accomplish this goal requires a multi-disciplinary approach. We have assembled a strong collaborative team with a proven track record that will have the necessary mechanistic, structural, synthetic, computational and cell biology experience to attack this problem. There are two specific aims in this proposal both focused on comprehensive studies of protozoal bifunctional TS-DHFR enzymes.

描述（由申请人提供）：在过去的十年中，在治疗由 HIV 感染引起的 AIDS 的抗病毒疗法方面取得了重大进展。目前，机会性感染是艾滋病患者痛苦和死亡的主要原因。其中许多感染是由寄生虫引起的，很少影响免疫功能正常的个体。不幸的是，针对 HIV-1 病毒的成功联合疗法仍然使大多数患者容易受到机会性寄生虫感染。很少有药物可用于治疗这些寄生虫感染。现有的药物缺乏选择性，导致宿主毒性、不良副作用以及由于耐药性的产生而无效。因此，需要确定新的靶向策略，最终可能导致更具选择性和更低毒性的治疗方法。该提案概述了机制和结构研究，重点关注仅存在于寄生虫中的独特双功能酶，这些酶可能作为发现用于治疗艾滋病患者机会性感染的新型抗寄生虫药物的潜在目标。 该提案的中心主题是，在分子水平上对寄生双功能 TS-DHFR 酶进行综合机制、结构和计算评估，将有助于确定这些独特双功能酶的新靶向策略，并提供必要的概念验证，以建立非活性位点抑制剂作为一种有效的新型治疗方法。该研究的长期目标是利用寄生虫酶和人类酶之间的独特差异，开发新型抗寄生虫药物来治疗机会性寄生虫感染。为了实现这一目标需要采取多学科的方法。我们组建了一支强大的协作团队，拥有良好的业绩记录，拥有解决这一问题所需的机械、结构、合成、计算和细胞生物学经验。该提案有两个具体目标，均侧重于原生动物双功能 TS-DHFR 酶的综合研究。