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: 10057413
• 负责人: Celia A. Schiffer
• 金额: $ 20.94万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057413
• 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.

靶向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)是第一个被发现感染人类的逆转录病毒 全世界数以百万计的人。HTLV-1是高度致癌的，感染可以导致生命- 对癌症构成威胁，并使炎症状况失效。最近在澳大利亚爆发了一场大规模疫情， 全球持续感染人群，并传播到非流行地区 移民局敦促立即采取行动解决这种在很大程度上被忽视的疾病。最近， 全球病毒网络工作组领导层强烈建议扩大对 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 自从近40年前发现HTLV-1以来，已经开发出针对HTLV-1的病毒。 尽管在酶学上相似，HTLV-1蛋白酶底物的特异性与 HIV-1蛋白水解酶。这阻止了目前的HIV-1蛋白水解酶抑制剂对 HTLV-1，尽管有些结合很弱。设计以底物为靶点的抑制剂 HTLV-1蛋白酶的外膜是开发高效和 强大的HTLV-1抑制剂。对底物包膜的表征也将揭示 高度被忽视的HTLV-1蛋白酶底物专一性的分子基础。翻译： 我们的战略，加上我们在艾滋病毒-1方面的丰富经验，将极大地惠及 抗HTLV-1小分子抑制剂的发现。