Design of Protease Inhibitors to Target HTLV-1

针对 HTLV-1 的蛋白酶抑制剂的设计

• 批准号: 10201509
• 负责人: Celia A. Schiffer
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-24 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201509
• 关键词: Active Sites; Address; Adopted; Advisory Committees; Amino Acid Sequence; Antiviral Agents; Aspartic Endopeptidases; Australia; Binding; Biological Assay; Cells; Cleaved cell; Collection; Coupled; Crystallization; Disease; Disease Outbreaks; Drug Design; Drug resistance; Evaluation; Evolution; FDA approved; Funding; Generations; Genomics; HIV-1; HIV-1 protease; Hepatitis C virus; Heterogeneity; Human; Human T-lymphotropic virus 1; Immigration; Infection; Inflammatory; Laboratories; Lead; Leadership; Life; Life Cycle Stages; Malignant Neoplasms; Molecular; Mutate; Peptide Hydrolases; Polyproteins; Population; Predisposition; Probability; Protease Inhibitor; Reagent; Reporting; Research; Research Support; Resistance; Retroviridae; Series; Shapes; Structure; Substrate Specificity; Therapeutic Agents; Translations; Viral; Virus; base; carcinogenicity; co-infection; design; experience; improved; inhibitor/antagonist; neglect; novel; pressure; prevent; prophylactic; scaffold; small molecule inhibitor

Design of Protease Inhibitors to Target HTLV-1 Human T cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus that infects millions of people worldwide. HTLV-1 is highly carcinogenic, and infection can lead to life- threatening cancers and disabling inflammatory conditions. A recent major outbreak in Australia, persistent infected populations over the globe, and spread to non-endemic regions with immigration urges immediate action to address this largely neglected disease. Recently, the Global Virus Network Task Force leadership has strongly recommended expanding research on HTLV-1. In stark contrast to the highly related HIV-1, no direct-acting antiviral (DAA) agents have been developed to target HTLV-1 since its discovery almost 40 years ago. Although enzymatically similar, the HTLV-1 protease substrate specificity is quite distinct from HIV-1 protease. This prevents the current HIV-1 protease inhibitors from being effective against HTLV-1, although some have very weak binding. Designing inhibitors to target the substrate envelope of HTLV-1 protease represents the best opportunity for developing a highly potent and robust HTLV-1 inhibitor. Characterization of the substrate envelope will also reveal the molecular basis of substrate specificity for the highly neglected HTLV-1 protease. Translation of our strategies coupled with our extensive experience with HIV-1 will immensely benefit the discovery of small molecule inhibitors against HTLV-1.

针对 HTLV-1 的蛋白酶抑制剂的设计 人类 T 细胞白血病病毒 1 型（HTLV-1）是第一个被识别的感染人类逆转录病毒 全球数百万人。 HTLV-1具有高度致癌性，感染可导致生命—— 威胁癌症并抑制炎症。近期澳洲爆发重大疫情， 全球范围内持续存在感染人群，并传播到非流行地区 移民局敦促立即采取行动解决这种基本上被忽视的疾病。最近， 全球病毒网络工作组领导层强烈建议扩大对病毒的研究 HTLV-1。与高度相关的 HIV-1 形成鲜明对比的是，没有直接作用的抗病毒 (DAA) 药物 自近 40 年前发现 HTLV-1 以来，已开发出针对 HTLV-1 的药物。 尽管酶学相似，但 HTLV-1 蛋白酶底物特异性与 HIV-1 蛋白酶。这使得目前的 HIV-1 蛋白酶抑制剂无法有效对抗 HTLV-1，尽管有些具有非常弱的结合力。设计靶向底物的抑制剂 HTLV-1 蛋白酶的包膜代表了开发高效且 强效 HTLV-1 抑制剂。基板包络的表征也将揭示 高度被忽视的 HTLV-1 蛋白酶底物特异性的分子基础。请先登录再添加翻译 我们的策略加上我们在 HIV-1 方面的丰富经验将极大地造福于 发现针对 HTLV-1 的小分子抑制剂。

项目成果

Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.

• DOI: 10.1021/acs.chemrev.0c00648
• 发表时间: 2021-03-24
• 期刊: Chemical reviews
• 影响因子: 62.1
• 作者: Matthew AN;Leidner F;Lockbaum GJ;Henes M;Zephyr J;Hou S;Rao DN;Timm J;Rusere LN;Ragland DA;Paulsen JL;Prachanronarong K;Soumana DI;Nalivaika EA;Kurt Yilmaz N;Ali A;Schiffer CA
• 通讯作者: Schiffer CA

Viral proteases: Structure, mechanism and inhibition.

• DOI: 10.1016/bs.enz.2021.09.004
• 发表时间: 2021
• 期刊: The Enzymes
• 作者: Zephyr J;Kurt Yilmaz N;Schiffer CA
• 通讯作者: Schiffer CA

Inhibiting HTLV-1 Protease: A Viable Antiviral Target.

• DOI: 10.1021/acschembio.0c00975
• 发表时间: 2021-03-19
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Lockbaum GJ;Henes M;Talledge N;Rusere LN;Kosovrasti K;Nalivaika EA;Somasundaran M;Ali A;Mansky LM;Kurt Yilmaz N;Schiffer CA
• 通讯作者: Schiffer CA

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.

SARS-CoV-2 主要蛋白酶与非共价抑制剂 ML188 复合物的晶体结构。

• DOI: 10.3390/v13020174
• 发表时间: 2021-01-25
• 期刊: Viruses
• 作者: Lockbaum GJ;Reyes AC;Lee JM;Tilvawala R;Nalivaika EA;Ali A;Kurt Yilmaz N;Thompson PR;Schiffer CA
• 通讯作者: Schiffer CA