Exploring Novel Targeting Strategies for AIDS Protozoal Pathogens

摘要 在过去的十年中，用于治疗由HIV感染引起的AIDS的抗病毒疗法已经取得了重大进展。目前，机会性感染是艾滋病患者痛苦和死亡的主要原因。 这些感染中有许多是由寄生虫引起的，这些寄生虫很少影响没有感染的个体。 免疫力低下不幸的是，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。几乎没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、不良副作用和由于产生耐药性而无效。因此，需要鉴定新的靶向策略，其可能最终导致更具选择性且毒性更小的治疗剂。该提案概述了机制和结构的研究，重点是独特的双功能酶目前只在寄生虫， 作为一个潜在的目标，发现新的抗寄生虫药物治疗艾滋病患者的机会性感染。 该提案的中心主题是，在分子水平上对寄生双功能TS-DHFR酶进行综合的机械、结构和计算评估，将有助于为这些独特的双功能酶确定新的靶向策略，并提供必要的概念验证，以建立非活性位点抑制剂作为有效的新型治疗方法。拟议研究的长期目标是利用寄生虫和人类酶之间的独特差异，开发新型抗寄生虫药物用于治疗机会性寄生虫感染。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合作团队，具有良好的业绩记录，将具有必要的机械，结构，合成，计算和细胞生物学经验， 解决这个问题。有两个具体的目标，在这个建议都集中在原生动物的双功能TS-DHFR酶的综合研究。

ABSTRACT 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.