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盐抗病毒药物，用于治疗耐药HIV感染。艾滋病毒耐药性，无论是获得性还是传播性，都非常普遍，是对有效治疗管理的重大挑战。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，替诺福韦是用于HIV感染的。无环核苷膦酸盐有几个缺点。作为一类药物，它们不能被口服吸收，它们对细胞膜的渗透受到双负电荷的高度限制，一旦进入体内，它们就会被肾近端小管中的活性转运体选择性地吸收，导致肾毒性。其中一些问题可以通过磷酸盐氧的酯化来克服。替诺福韦二oproxil可以改善口服吸收，但二oproxil被去除，带双重负电荷的替诺福韦循环，使肾脏暴露于潜在的肾毒性，并保留了细胞膜穿透的限制。为了解决这些缺点，我们开发了一种新的方法，涉及到一个单一的磷酸盐氧与烷氧烷基的酯化反应。这增加了口服吸收，细胞渗透，并提高抗病毒活性3或更多的对数在体外。迄今为止，我们已经确定了五种新型的、口服活性的高效无环核苷膦酸烷氧烷基酯，它们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。我们提出详细的临床前评估，以扩大耐药艾滋病毒变异的范围，包括TAMS， M184V, K65R， 69插入，151复杂和多重耐药艾滋病毒突变和临床分离株。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估，目的是使最有希望的新药进入耐药HIV感染的IND状态。摘要：在服用抗艾滋病毒药物的艾滋病患者中，出现耐药性的比例很高，并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治疗耐药HIV感染的五种高效新型抗病毒膦酸盐之一。

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.