Generating SEVI disaggregases to prevent HIV infection

生成 SEVI 分解以预防 HIV 感染

• 批准号: 8501616
• 负责人: James Shorter
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501616
• 关键词: Academic Medical Centers; Acquired Immunodeficiency Syndrome; Amyloid; Amyloid Fibrils; Antiviral Agents; Binding; Biochemical; Cell Culture Techniques; Cells; Cessation of life; Coupled; Engineering; Enhancers; Enzymes; Fiber; Foundations; Gel; Generic Drugs; Genotype; Germany; Goals; HIV; HIV Infections; HIV-1; Human; Infection; Jurkat Cells; Methods; Microbe; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Peptide Hydrolases; Peptides; Prions; Proteins; Public Health; Rattus; Reaction; Route; Seminal fluid; Sexual Transmission; Solutions; Structure; Sum; System; T-Lymphocyte; Tropism; Variant; Viral; Virion; Virus; Virus Diseases; Yeasts; amyloid formation; base; beta pleated sheet; combat; conformer; empowered; microbicide; novel; pandemic disease; polypeptide; prevent; professor; prostatic fraction Acid phosphatase isoenzyme; small molecule; sup35; synthetic peptide; synuclein; transmission process; weapons; yeast prion

DESCRIPTION (provided by applicant): Human immunodeficiency virus type-1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), has infected ~60 million people worldwide and caused over 25 million deaths. Sexual transmission is the major route of HIV-1 infection and factors that promote this infectious route have recently been identified in semen. Fragments of prostatic acid phosphatase are a major component of semen and form amyloid fibrils that bind HIV virions and can promote infection by several orders of magnitude up to 105-fold. Therefore, a potential preventative strategy is to deploy agents that eliminate these amyloid forms, which are termed Semen-derived Enhancer of Virus Infection (SEVI) fibrils. Unfortunately, amyloid fibrils are notoriously stable and difficult to eradicate. In other settings, they are connected with various fatal neurodegenerative disorders. However, various microbes have harnessed the amyloid form for beneficial purposes, and systems have evolved that can rapidly reverse amyloid formation. One natural protein has emerged that resolves amyloid fibrils with unprecedented alacrity: the protein disaggregase, Hsp104. Hsp104 rapidly solubilizes amyloid forms of several proteins, including yeast prion proteins Sup35 and Ure2, as well as ?-synuclein, which forms amyloid fibrils in Parkinson's disease. We hypothesize that Hsp104 or SEVI-optimized variants can be generated to rapidly dissolve or remodel SEVI fibrils and thereby diminish SEVI-enhanced HIV infection. Thus, we aim to: (1) Develop Hsp104 variants that rapidly disassemble SEVI fibrils~ and (2) Determine whether disassembled products have diminished ability to promote HIV infection. These studies will provide the foundations for developing SEVI disaggregases as preventative agents with the ultimate goal of incorporating them into a gel or solution that dissolves SEVI fibrils in semen and reduces sexual transmission of HIV. The ability to reverse fibril formation (rather than simply inhibit it) and blck sexual transmission of HIV will provide a powerful and much needed weapon against the global HIV/AIDS pandemic. Our approach of targeting a host protein conformer (SEVI fibrils) is fundamentally different from traditional microbicidal approaches that target the virus, and this strategy is anticipated to synergize with direct antiviral strategies.

描述（由申请人提供）：1 型人类免疫缺陷病毒 (HIV-1) 是获得性免疫缺陷综合症 (AIDS) 的病原体，已感染全世界约 6000 万人，并导致超过 2500 万人死亡。性传播是 HIV-1 感染的主要途径，最近在精液中发现了促进这种感染途径的因素。前列腺酸性磷酸酶的片段是精液的主要成分，可形成淀粉样原纤维，与 HIV 病毒体结合，可将感染促进几个数量级，高达 105 倍。因此，一种潜在的预防策略是部署消除这些淀粉样蛋白形式的药物，这些淀粉样蛋白形式被称为精液源性病毒感染增强剂（SEVI）原纤维。不幸的是，众所周知，淀粉样原纤维非常稳定且难以根除。在其他方面 在环境中，它们与各种致命的神经退行性疾病有关。然而，各种微生物已经利用淀粉样蛋白的形式达到有益的目的，并且已经进化出可以快速逆转淀粉样蛋白形成的系统。一种天然蛋白质已经出现，它能够以前所未有的速度解决淀粉样原纤维：蛋白质解聚酶 Hsp104。 Hsp104 可快速溶解多种蛋白质的淀粉样蛋白形式，包括酵母朊病毒蛋白 Sup35 和 Ure2，以及在帕金森病中形成淀粉样原纤维的 β-突触核蛋白。我们假设可以产生 Hsp104 或 SEVI 优化变体来快速溶解或重塑 SEVI 原纤维，从而减少 SEVI 增强的 HIV 感染。因此，我们的目标是：(1) 开发能够快速分解 SEVI 原纤维的 Hsp104 变体，以及 (2) 确定分解的产物是否会降低促进 HIV 感染的能力。这些研究将为开发 SEVI 分解酶作为预防剂奠定基础，最终目标是将它们纳入凝胶或溶液中，溶解精液中的 SEVI 原纤维并减少 HIV 的性传播。逆转原纤维形成（而不是简单地抑制它）和阻止艾滋病毒性传播的能力将为对抗全球艾滋病毒/艾滋病大流行提供强大且急需的武器。我们针对宿主蛋白构象异构体（SEVI原纤维）的方法与针对病毒的传统杀微生物方法有根本不同，并且该策略预计将与直接抗病毒策略产生协同作用。

项目成果

Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.

• DOI: 10.1021/jacs.0c06400
• 发表时间: 2020-10-07
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Weil T;Groß R;Röcker A;Bravo-Rodriguez K;Heid C;Sowislok A;Le MH;Erwin N;Dwivedi M;Bart SM;Bates P;Wettstein L;Müller JA;Harms M;Sparrer K;Ruiz-Blanco YB;Stürzel CM;von Einem J;Lippold S;Read C;Walther P;Hebel M;Kreppel F;Klärner FG;Bitan G;Ehrmann M;Weil T;Winter R;Schrader T;Shorter J;Sanchez-Garcia E;Münch J
• 通讯作者: Münch J