Multivalent Env gp120 Targeting Gold Nanoparticle Virucides of HIV-1

多价 Env gp120 靶向金纳米粒子 HIV-1 病毒

• 批准号: 8329863
• 负责人: IRWIN M CHAIKEN
• 金额: $ 28.53万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329863
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Affinity; Antiviral Agents; Binding; Binding Sites; Biological Assay; Cell fusion; Cell membrane; Cells; Characteristics; DNA Sequence Rearrangement; Data; Defensins; Dengue; Dependence; Development; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epitopes; Exhibits; Extravasation; Goals; Gold; Gut associated lymphoid tissue; HIV Envelope Protein gp120; HIV-1; Hydrogels; Infection; Infection prevention; Influenza; Intervention; Lead; Ligands; Measures; Membrane; Membrane Proteins; Modification; Molecular; Mutation; Peptides; Prevention; Process; Property; Proteins; RNA-Directed DNA Polymerase; Receptor Cell; Rupture; Site; Surface; Therapeutic; Time; Triazoles; Vagina; Virion; Virus; Virus Diseases; Virus Inactivation; Work; antileukoprotease; antimicrobial; base; density; design; env Gene Products; flexibility; human SLPI protein; improved; inhibitor/antagonist; innovation; interdisciplinary approach; microbicide; nanoassembly; nanoparticle; nanoscience; pathogen; peptide A; protein complex; public health relevance; receptor binding; response; tool; virucide; virus envelope

DESCRIPTION (provided by applicant): This project addresses a major goal to identify HIV-1 antagonists that could inactivate the virus specifically before host cell encounter. Inhibition of he initial entry of HIV-1 into host cells remains a compelling and yet elusive means to prevent infection and spread of the virus. Entry is dependent on the ability of the virus envelope protein spike to interact with specific cell receptors in a multistage process that triggers conformational rearrangements in Env and consequent fusion of virus and cell membrane to deliver virus contents to the host. A peptide triazole class of entry inhibitors has been identified previously and found to be able to bind to HIV-1 gp120 with nanomolar affinity, to suppress protein ligand interactions of the Env protein at both its CD4 and co-receptor binding sites and to inhibit cell infection by a broad range of virus subtypes. Strikingly, we have found recently that a multivalent form of the peptide triazole KR13 displayed on gold nanoparticles (AuNPs) is able to disrupt virus particles in the absence of host cells, causing leakage of the internal protein p24 and exhibiting strong antiviral activity. We hypothesize that the multivalent peptide triazole AuNPs are capitalizing on the intrinsic metastability of the virus Env, and that optimizing such nanoassemblies based on modulating their fundamental properties can help identify HIV-1-specific virucidal agents to use in AIDS treatment and prevention by promoting cell-free virus rupture and inactivation. Based on these findings, the Specific Aims of this proposed project are to (1) determine rules of spatial geometry and surface rigidity of gold nanoparticle - peptide triazole (AuNP-PT) that promote cell-free HIV-1 virolysis; (2) determine mechanistic properties of AuNP-PT induced HIV-1 virolysis and its relationship to the pathogenic process of virus cell infection; (3) establish fundamental stability and cell transport properties of AuNP-KR13 nanoconstructs. Overall, this work will derive principles for designing multivalent Env-targeting NP's to enable virucidal actions that are specific for HIV-1. The NP's will help expand understanding of the extent to which the Env metastability that is critical for pathogenic host cel entry can be hijacked to develop tools for HIV-1 therapeutics and microbicides. The results will provide precedent for how other gp120 inhibitor-NP compositions can be devised for HIV-1 virus inactivation as well as how ligand-specific pathogen rupture can potentially be achieved for other viruses that contain metastable prefusion surface protein complexes. PUBLIC HEALTH RELEVANCE: This project will establish an innovative, multidisciplinary approach, combining nanoscience engineering and HIV-1 biomolecular strategies, to inactivate HIV-1 virus before cell encounter. This work will help stimulate development of specific virolytic agents for AIDS prevention and treatment.

描述（由申请人提供）：该项目解决了一个主要目标，以识别可能在宿主细胞相遇之前特别使病毒失活的HIV-1拮抗剂。抑制HIV-1进入宿主细胞的初步进入仍然是一种令人信服但难以捉摸的手段，可防止病毒感染和传播。输入取决于病毒包膜蛋白峰在多阶段过程中与特定细胞受体相互作用的能力，从而触发构象 ENV的重排以及随之而来的病毒和细胞膜融合，以向宿主提供病毒含量。先前已经鉴定出肽三唑三唑的入口抑制剂，并能够与HIV-1 GP120与纳摩尔亲和力结合，以抑制ENV蛋白在其CD4和共核能结合位点的蛋白配体相互作用，并通过病毒亚型的广泛范围的细胞感染抑制细胞感染。令人惊讶的是，我们最近发现，在没有宿主细胞的情况下，在金纳米颗粒上显示的一种多价形式的肽kr13（AUNPS）能够破坏病毒颗粒，从而导致内部蛋白质p24泄漏并表现出强抗病毒活性。我们假设多价肽三唑Aunps正在利用病毒ENV的内在稳定性，并且基于基于其基本特性调节其基本特性的此类纳米组件的优化可以帮助识别HIV-1特异性病毒药物，以通过促进无细胞病毒毒素破裂和预防艾滋病治疗和预防。基于这些发现，该提出的项目的具体目的是（1）确定金纳米颗粒 - 肽三唑（AUNP-PT）的空间几何形状和表面刚度规则，从而促进无细胞的HIV-1毒化； （2）确定AUNP-PT诱导的HIV-1毒化及其与病毒细胞感染的致病过程的机理特性； （3）建立AUNP-KR13纳米结构的基本稳定性和细胞转运特性。总体而言，这项工作将得出设计多价靶标NP的原则，以实现针对HIV-1特定的病毒作用。 NP将有助于扩大对致病宿主进入至关重要的ENV亚稳定性的了解，以开发用于HIV-1治疗剂和杀菌剂的工具。该结果将为如何设计用于HIV-1病毒灭活的其他GP120抑制剂-NP组合物以及如何为包含亚抗体预染料表面蛋白复合物的其他病毒而实现配体特异性病原体破裂的先例。 公共卫生相关性：该项目将建立一种创新的，多学科的方法，将纳米科学工程和HIV-1生物分子策略结合起来，以使HIV-1病毒在相遇之前灭活。这项工作将有助于刺激用于预防和治疗的特定毒液的开发。