New Anti-HIV Agents from Evolutionary Chemistry

描述（由申请人提供）：进化化学tm （EC）是一种潜在的革命性方法，可以发现含铅小分子药物。EC将小分子合成和高通量筛选的步骤整合到一个系统中。通过利用RNA催化化学转化的能力，可以产生类似药物的分子，一个巨大的小分子化学文库可以被组装起来，其中包含10万到10亿个潜在的先导化合物。通过小分子文库组装，进化压力和生物催化剂扩增的迭代循环，确定了最佳执行所需功能的化合物。我们建议将EC方法应用于已验证的HIV药物靶点天冬氨酸蛋白酶，因为迫切需要新的HIV治疗方法，因为通过这种方法的成功将展示EC的优势：一种能够完全测量已经成功的核心结构周围的小分子/蛋白质界面的方法，并要求所选化合物表现出规定的性质。重要的是，在EC的分配过程中施加的进化压力将增加HIV蛋白酶抑制剂药物导联被确定的可能性，这些导联将对对当前治疗有抗性的临床分离株有活性，以及增加这些化合物具有良好生物利用度和代谢稳定性的可能性。

DESCRIPTION (provided by applicant): Evolutionary ChemistryTM (EC) is a potentially revolutionary approach to the discovery of lead small molecule pharmaceuticals. EC integrates the steps of small molecule synthesis and high throughput screening into a single system. By utilizing the demonstrated ability of RNA to catalyze chemical transformations that can create drug-like molecules, an enormous small molecule chemical library can be assembled that contains one hundred thousand to one billion potential lead compounds. Through iterative cycles of small molecule library assembly, evolutionary pressure and biocatalyst amplification, compounds that best perform a desired function are identified. We propose to apply the EC methodology to the validated HIV drug target, aspartyl protease, because of the urgent need for new HIV therapies and because success through this approach would demonstrate the advantages of EC: a methodology capable of completely surveying the small molecule/protein interface around already successful core structures and of demanding that selected compounds exhibit prescribed properties. Importantly, evolutionary pressures applied during the partitioning component of EC will increase the likelihood that the HIV protease inhibitor drug leads that are identified will be active against clinical isolates resistant to current therapies, as well as increasing the probability that these compounds will have favorable bioavailability and metabolic stability.