POTENT NEW NUCLEOSIDE ANALOGS FOR DRUG RESISTANT HIV

描述(申请人提供)：描述：本提案的总体目标是从五种先导化合物中选择一种新型的、高效的无环核苷膦酸盐抗病毒药物，用于治疗抗药性艾滋病毒感染。艾滋病毒耐药性，无论是获得性的还是传播性的，都非常普遍，是有效治疗管理的重大挑战。三种无环核苷膦被批准用于病毒疾病的口服治疗；其中，替诺福韦用于艾滋病毒感染。无环核苷膦有几个缺点。作为一类，它们不被口服吸收，它们对细胞膜的穿透受到双负电荷的高度限制，一旦进入体内，它们就被肾脏近端小管上的活性转运蛋白选择性地摄取，造成肾毒性。这些问题中的一些可以通过将膦酸氧酯化来克服。替诺福韦可改善口服吸收，但异丙酚被清除，双负电荷替诺福韦循环，使肾脏暴露于潜在的肾毒性，并保留细胞膜穿透的限制。为了解决这些缺点，我们开发了一种新的方法，涉及到单膦酸氧与烷氧基的酯化反应。这增加了口服吸收，细胞渗透，并在体外增强了3个或更多的对数抗艾滋病毒的抗病毒活性。到目前为止，我们已经鉴定了五种新型的、具有口服活性的高效烷氧基烷基酯，它们对HIV-1具有纳摩尔或皮摩尔范围的活性，并且对一组耐药的HIV变异体具有完全或几乎完全的活性。我们建议对扩大的耐药HIV变异株进行详细的临床前评估，包括TAMS、M184V、K65R、69插入、151复杂和多药耐药HIV突变株和临床分离株。最有希望的候选药物将被选中进行详细的代谢、药代动力学和毒理学评估，目标是将最有希望的新药推向抗药性艾滋病毒感染的IND状态。Lay摘要：在服用抗HIV药物的艾滋病患者中，有很高比例会产生耐药性，并可能导致治疗效果的丧失。这项建议是为了评估和开发我们设计的用于治疗抗药性HIV感染的五种高效新型抗病毒磷酸盐之一。

DESCRIPTION (provided by applicant): Description: The overall goal of this proposal is to select from five lead compounds, a novel, highly potent acyclic nucleoside phosphonate antiviral for the treatment of drug resistant HIV infection. HIV drug resistance, both acquired and transmitted, is highly prevalent and represents a major challenge to effective therapeutic management. Three acyclic nucleoside phosphonates are approved for oral therapy of viral diseases; of these, tenofovir is marketed for HIV infection. Acyclic nucleoside phosphonates have several drawbacks. As a class, they are not absorbed orally, their penetration of the cellular membrane is highly restricted by their double negative charge and, once in the body, they are selectively taken up by an active transporter in kidney proximal tubules causing nephrotoxicity. Some of these problems can be overcome by esterifying the phosphonate oxygens. Tenofovir disoproxil improves oral absorption, but the disoproxils are removed and doubly negatively charged tenofovir circulates, exposing the kidney to potential nephrotoxicity and retaining the limitation of cell membrane penetration. To address these drawbacks, we have developed a novel approach which involves esterification of a single phosphonate oxygen with an alkoxyalkyl group. This increases oral absorption, cell penetration and enhances antiviral activity against HIV by 3 or more logs in vitro. To date, we have identified five novel, orally active highly potent alkoxyalkyl esters of acyclic nucleoside phosphonates which are active in the nanomolar or picomolar range against HIV-1 and have full or nearly full activity against a panel of drug resistant HIV variants. We propose detailed preclinical evaluation against an expanded panel of drug resistant HIV variants including TAMS, M184V, K65R, 69 insert, 151 complex and multidrug resistant HIV mutants and clinical isolates. The most promising candidate will be selected for detailed metabolic, pharmacokinetic, toxicologic evaluations with the goal of bringing the most promising new drug toward IND status for drug resistant HIV infection. Lay summary: Drug resistance develops in a high percentage of AIDS patients taking anti-HIV drugs and may lead to loss of therapeutic effectiveness. This proposal is to evaluate and develop one of five highly potent new antiviral phosphonates of our design for treatment of drug resistant HIV infection.