Specificity Studies of HIV and HTLV Proteases

HIV 和 HTLV 蛋白酶的特异性研究

• 批准号: 6747662
• 负责人: Irene T Weber
• 金额: $ 4.03万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747662
• 关键词: Europe; antiviral agents; aspartic endopeptidases; cooperative study; drug resistance; human T cell lymphotropic virus type 1; human immunodeficiency virus 1; hydrolysis; molecular cloning; molecular dynamics; mutant; protease inhibitor; protein purification; protein structure function; virus protein

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.

描述（由申请人提供）：这项研究将主要完成 在匈牙利作为 NIH 拨款的延伸 # R01 GM62920。人体免疫缺陷 1 型病毒 (HIV-1) 蛋白酶对于病毒复制至关重要，并且已被证明 抗病毒药物治疗艾滋病的有效靶点。但是，从长远来看 目前蛋白酶抑制剂作为治疗剂的有效性有限 由于蛋白酶的耐药变体的快速发展。这是 需要了解其作用的分子基础 HIV-1 蛋白酶的抑制剂抗性变体，以开发新的 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 蛋白酶抑制剂和克服该问题的治疗策略 耐药性。家长补助金中提出的特异性研究将是 扩展到涵盖更广泛的寡肽底物，以便更多 全面表征抑制剂抗性 HIV-1 蛋白酶突变体。 此外，关于特异性的分子基础的新研究 提出了相关的人类 T 细胞白血病病毒 1 型 (HTLV-1) 蛋白酶。 这些研究将结合底物动力学分析 水解、诱变和分子建模研究。了解 共同特征和差异的分子基础 各种逆转录病毒蛋白酶的特异性，包括抑制剂耐药性 HIV-1蛋白酶的变体将有助于广谱设计 蛋白酶抑制剂。这些新型抑制剂将在以下领域得到应用： 治疗艾滋病和逆转录病毒引起的其他人类疾病。

项目成果

Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases.

• DOI: 10.1099/vir.0.82704-0
• 发表时间: 2007-07
• 期刊: The Journal of general virology
• 作者: Tamás Sperka;Gabriella Miklóssy;Y. Tie;P. Bagossi;G. Zahuczky;P. Boross;Krisztina Matúz;R. Harrison;I. Weber;J. Tözsér

The protease of human T-cell leukemia virus type-1 is a potential therapeutic target.

人类 T 细胞白血病病毒 1 型的蛋白酶是一个潜在的治疗靶点。

• DOI: 10.2174/138161207780618849
• 发表时间: 2007
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Tözsér,József;Weber,IreneT
• 通讯作者: Weber,IreneT