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）：人类免疫缺陷病毒类型1（HIV-1）是获得性免疫缺陷综合征（AIDS）的病因（HIV-1），已感染了全球约6000万人，造成超过2500万人死亡。性传播是HIV-1感染的主要途径，并且最近在精液中发现了促进这种传染性途径的因素。前列腺酸性磷酸酶的片段是精液的主要成分，形成了结合HIV病毒体的淀粉样蛋白原纤维，并可以通过多个数量级促进感染，最高为105倍。因此，潜在的预防策略是部署消除这些淀粉样形式的剂，这些淀粉样形式称为病毒感染（SEVI）原纤维的精液增强子。不幸的是，淀粉样蛋白原纤维众所周知稳定且难以消除。在其他 设置，它们与各种致命的神经退行性疾病有关。但是，各种微生物都利用了淀粉样蛋白的形式来实现有益的目的，并且系统可以快速逆转淀粉样蛋白形成。一种天然蛋白质已经出现，它可以用前所未有的酸度解决淀粉样蛋白原纤维：蛋白质分裂酶HSP104。 HSP104迅速溶解了几种蛋白质的淀粉样蛋白形式，包括酵母prion蛋白Sup35和Ure2，以及？-synnuclein，哪些在帕金森氏病中形成淀粉样蛋白原纤维。我们假设可以生成Hsp104或Sevi优化变体以迅速溶解或重塑Sevi纤维，从而减少SEVI增强HIV感染。因此，我们的目的是：（1）开发迅速拆卸Sevi纤维〜的HSP104变体，（2）确定拆卸产品是否降低了促进HIV感染的能力。这些研究将为开发SEVI分类酶作为预防剂的基础，其最终目标是将其纳入溶解SEVI原纤维的凝胶或溶液中，并减少HIV的性传播。逆转原纤维形成的能力（而不是简单地抑制它）和艾滋病毒的BLCK性传播将为全球艾滋病毒/艾滋病大流行提供强大而急需的武器。我们针对宿主蛋白质构象异构体（SEVI原纤维）的方法与靶向病毒的传统杀菌方法根本不同，并且预计该策略将与直接的抗病毒策略协同作用。

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