Exploring Novel Targeting Strategies for AIDS Protozoal Pathogens

描述(由申请人提供)：在过去的十年中，抗病毒疗法在治疗艾滋病毒感染引起的艾滋病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。这些感染中的许多是由寄生虫引起的，这些寄生虫很少影响没有免疫受损的人。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。目前治疗这些寄生虫感染的药物寥寥无几。现有的药物缺乏选择性，导致宿主毒性、不良副作用，以及由于产生耐药性而无效。因此，有必要确定新的靶向策略，这些策略最终可能导致更具选择性和毒性更低的治疗方法。这项建议概述了机制和结构研究，重点是只存在于寄生虫中的独特的双功能酶，这些酶可能成为发现治疗艾滋病患者机会性感染的新型抗寄生虫药物的潜在靶点。这项建议的中心主题是，在分子水平上对寄生的双功能TS-DHFR酶进行综合的机制、结构和计算评估，将有助于确定这些独特的双功能酶的新靶向策略，并提供必要的概念证明，以建立非活性部位抑制剂作为一种有效和新颖的治疗方法。这项拟议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，开发用于治疗机会性寄生虫感染的新型抗寄生虫药物。要实现这一目标，需要采取多学科的方法。我们已经组建了一个强大的协作团队，拥有经过验证的记录，将拥有必要的机械、结构、合成、计算和细胞生物学经验来解决这个问题。这项提案有两个具体目标，都集中在原生动物双功能TS-DHFR酶的综合研究上。 公共卫生相关性：机会性感染是艾滋病患者痛苦和死亡的主要原因。这些感染中的许多是由寄生虫引起的，这些寄生虫很少影响没有免疫受损的人。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，迫切需要新的疗法。

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. PUBLIC HEALTH RELEVANCE: 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 and new therapies are desperately needed.