Structure activity and structure property relationships for novel anti-HIV agents

描述(申请人提供)：逆转录酶(RT)是一种必需的酶，通过聚合将病毒RNA基因组复制到双链DNA中，这是HIV-1感染所需的过程。HIV-1中的几种酶，包括RT，是高效抗逆转录病毒疗法(HAART)的药物靶点。非核苷和非核苷酸逆转录酶抑制剂(NNRTI)是与3-4种额外的抗病毒药物联合使用的治疗药物，它们协同作用诱导感染患者的病毒载量抑制。目前，FDA批准的针对RT的NNRTI有5种，包括奈韦拉平、地拉韦林、依沙韦林、依特拉韦林和利培韦林。然而，目前的NNRTI有几个限制，例如长期使用带来的耐药性和毒性问题。设计和开发具有改进的耐药性和安全性的新的NNRTI对于克服HIV-1治疗失败至关重要。在过去的几年里，我们结合了机理研究、计算化学和基于结构的药物设计，开发了几种新的化合物作为潜在的NNRTI。我们最近设计了一种NNRTI化合物，它对HIV-1有活性，细胞毒性的治疗指数为18万。这种化合物的EC50为55 pm，是迄今为止针对HIV-1的最有效的抗病毒药物。为了将这些化合物优化为潜在的候选药物，本建议旨在开发结构活性关系(SAR)和结构性质关系(SPR)。稳态前动力学将决定主要NNRTI化合物和RT酶的结合亲和力测量。除了结合亲和力外，主要的NNRTI和RT酶的共结晶将为酶-抑制剂相互作用和SAR提供结构解释。将使用一系列体外分析和药理学技术来确定先导化合物的SPR。结构性质测量包括亲脂性、动力学溶解度、渗透性和代谢稳定性。将SAR和SPR用于领先的NNRTI化合物将优先考虑未来的开发，并为有效的NNRTI的合理药物设计提供结构信息。

DESCRIPTION (provided by applicant): Reverse transcriptase (RT) is an essential enzyme that copies the viral RNA genome into double stranded DNA via polymerization, a process required for HIV-1 infection. Several enzymes in HIV-1, including RT, are drug targets for highly active antiretroviral therapies (HAART). Non-nucleoside and non-nucleotide RT inhibitors (NNRTIs) are therapeutics prescribed in combination with 3-4 additional antiviral agents that work synergistically to induce viral load suppression in infected patients. Currently, there are fie FDA approved NNRTIs targeting RT, which include nevirapine, delaviridine, efavirenz, etravirine, and rilpivirine. However, there are several limitations to current NNRTIs such as resistance and toxicity issues from long-term usage. The design and development of new NNRTIs with improved resistance and safety profiles is crucial to overcome HIV-1 treatment failure. Over the last few years, we have developed several new compounds as potential NNRTIs using a combination of mechanistic studies, computational chemistry, and structure-based drug design. We have recently designed an NNRTI compound that is active against HIV-1 and has a therapeutic index of 180,000 for cellular toxicity. With an EC50 of 55 pM, this compound emerges as the most potent antiviral agent targeting HIV-1 to date. In order to optimize these compounds into potential drug candidates, this proposal aims to develop structure activity relationships (SAR) and structure property relationships (SPR). Pre-steady state kinetics will determine binding affinity measurements for leading NNRTI compounds and the RT enzyme. In addition to binding affinities, co-crystallization of leading NNRTIs and the RT enzyme will provide a structural interpretation for enzyme-inhibitor interactions and SAR. A series of in vitro analytical and pharmacological techniques will be used to determine SPR for leading compounds. Structure property measurements to be determined include lipophilicity, kinetic solubility, permeability, and metabolic stability. The combination of both SAR and SPR for leading NNRTI compounds will prioritize future development and provide structural information for rational drug design of efficacious NNRTIs.