Specificity Studies of HIV and HTLV Proteases

描述(由申请人提供)：本研究将主要完成 在匈牙利，作为美国国立卫生研究院#R01 GM62920补助金的延伸。人类免疫缺陷 1型病毒(HIV-1)蛋白水解酶是病毒复制所必需的，并且已经证明 抗病毒药物治疗艾滋病的有效靶点。但是，从长远来看 目前作为治疗剂的蛋白酶抑制剂的有效性有限 由快速发展的抗药性变异体的蛋白酶。它是 必须了解的分子基础的行动 HIV-1蛋白水解酶耐药变异体的研究 抑制剂和新的治疗策略。家长提案的目的是 阐明HIV-1耐药变异体作用的分子基础 通过比较所选突变体的结构和活性 HIV-1和劳斯肉瘤病毒蛋白酶。长期目标是预测新的 蛋白水解酶抑制剂及其治疗策略 抗药性。在家长拨款中建议的专一性研究将是 扩展到涵盖更广泛的寡肽底物，以获得更多 对具有抑制剂抗性的HIV-1蛋白酶突变体进行充分鉴定。 此外，对该病毒特异性的分子基础的新研究 提出了相关的人T细胞白血病病毒1型(HTLV-1)蛋白水解酶。 这些研究将结合底物的动力学分析 水解、诱变和分子模拟研究。了解 生物多样性的共同特征和差异的分子基础 包括抑制剂抗性在内的多种逆转录病毒蛋白酶的特异性 HIV-1蛋白酶的变种将促进广谱设计 蛋白酶抑制剂。这些新的抑制剂将在 治疗艾滋病和其他由逆转录病毒引起的人类疾病。

DESCRIPTION (Provided by the applicant): This research will be done primarily in Hungary as an extension of NIH grant # R01 GM62920. Human immunodeficiency virus type 1 (HIV-1) protease is essential for viral replication and has proved an effective target for antiviral drugs to treat AIDS. But, the long term effectiveness of current protease inhibitors as therapeutic agents is limited by the rapid development of drug-resistant variants of the protease. It is necessary to understand the molecular basis for the action of the inhibitor-resistant variants of HIV-1 protease in order to develop new inhibitors and new therapeutic strategies. The aim of the parent proposal is to elucidate the molecular basis for the action of resistant variants of HIV-1 protease by comparing the structures and activities of selected mutants of HIV-1 and Rous sarcoma virus proteases. The long term aim is to predict new protease inhibitors and therapeutic strategies to overcome the problem of drug-resistance. The specificity studies proposed in the parent grant will be extended to cover a broader set of oligopeptide substrates in order to more fully characterize the inhibitor-resistant HIV- 1 protease mutants. Furthermore, new studies on the molecular basis for the specificity of the related human T-cell leukemia virus type 1 (HTLV-1) protease are proposed. These studies will use a combination of kinetic analysis of substrate hydrolysis, mutagenesis, and molecular modeling studies. Understanding the molecular basis of the common characteristics and differences in the specificity of various retroviral proteases including inhibitor resistanl variants of HIV-1 protease will facilitate the design of broad spectrum protease inhibitors. These new inhibitors will have applications in the treatment of AIDS and other human diseases caused by retroviruses.