POTENT NEW NUCLEOSIDE ANALOGS FOR DRUG RESISTANT HIV

描述（由申请人提供）：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、高效的无环核苷膦酸酯抗病毒药物，用于治疗耐药性HIV感染。艾滋病毒的抗药性，无论是获得性还是传播性，都非常普遍，对有效的治疗管理构成了重大挑战。三种无环核苷膦酸盐被批准用于病毒性疾病的口服治疗;其中，替诺福韦用于HIV感染。无环核苷膦酸酯具有几个缺点。作为一类，它们不能口服吸收，它们对细胞膜的渗透受到其双负电荷的高度限制，一旦进入体内，它们就被肾近端小管中的活性转运蛋白选择性摄取，导致肾毒性。这些问题中的一些可以通过使膦酸酯氧脱水来克服。替诺福韦二异丙酯改善口服吸收，但二异丙酯被去除，带双负电荷的替诺福韦循环，使肾脏暴露于潜在的肾毒性，并保留细胞膜渗透的限制。为了解决这些缺点，我们已经开发了一种新的方法，该方法涉及用烷氧基烷基酯化单个膦酸酯氧。这增加了口服吸收，细胞渗透，并在体外将抗HIV的抗病毒活性提高了3个或更多个对数。迄今为止，我们已经鉴定了五种新型的口服活性的高效无环核苷膦酸酯的烷氧基烷基酯，其在纳摩尔或皮摩尔范围内对HIV-1具有活性，并且对一组耐药HIV变体具有完全或几乎完全的活性。我们提出了针对扩大的耐药HIV变体组（包括TAMS、M184 V、K65 R、69个插入物、151个复杂和多药耐药HIV突变体和临床分离株）的详细临床前评价。将选择最有希望的候选药物进行详细的代谢、药代动力学和毒理学评价，目的是使最有希望的新药进入IND状态，用于治疗耐药HIV感染。摘要：在服用抗艾滋病毒药物的艾滋病患者中，耐药性的发生率很高，可能导致治疗效果的丧失。本提案旨在评估和开发我们设计的五种高效新型抗病毒膦酸盐之一，用于治疗耐药HIV感染。

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.