Glycopolymer Inhibitors of Heparan Sulfate Proteoglycan Binding Pathogens

硫酸乙酰肝素蛋白多糖结合病原体的糖聚合物抑制剂

• 批准号: 10684252
• 负责人: KATHERINE D MCREYNOLDS
• 金额: $ 10.65万
• 依托单位: CALIFORNIA STATE UNIVERSITY SACRAMENTO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684252
• 关键词: 2019-nCoV; Affect; Affinity; Alkynes; Antiviral Agents; Architecture; Azides; Binding; Binding Proteins; Biological; Biological Assay; Businesses; COVID-19; COVID-19 assay; COVID-19 pandemic; Carbohydrates; Cell Line; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Charge; China; Computing Methodologies; Death Rate; Dendrimers; Development; Disease; Electrons; Electrostatics; Energy Transfer; Enzyme-Linked Immunosorbent Assay; Evaluation; FDA Emergency Use Authorization; Future; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Heparan Sulfate Proteoglycan; Herd Immunity; In Vitro; Infection; Length; Life; Link; Location; Luciferases; Measures; Membrane Glycoproteins; Methods; Morbidity - disease rate; Outcome; Oximes; Patients; Persons; Polymers; Porphyrins; Positron-Emission Tomography; Process; Proteins; Recording of previous events; SARS-CoV-2 spike protein; Sulfate; Sulfur; Time; Vaccines; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Vulnerable Populations; Work; Zoonoses; copolymer; cost; cross reactivity; current pandemic; cycloaddition; cytotoxicity; design; design,build,test; fighting; future pandemic; illness length; improved; inhibitor; innovation; iterative design; molecular dynamics; monomer; mortality; novel; pandemic disease; pathogen; prevent; receptor; remdesivir; school closure; screening; sugar

PROJECT SUMMARY/ABSTRACT The current COVID-19 pandemic has resulted in millions of infections and over 2 million deaths worldwide since SARS-CoV-2 emerged in Wuhan, China in December of 2019. This pandemic has revealed a significant treatment gap in the ability to minimize the morbidity and mortality of those infected through the use of anti-viral drugs. Currently only remdesivir has been granted Emergency Use Authorization (EUA) by the FDA, but requires IV administration for 5-10 days at high cost, and has not demonstrated a significant reduction in the length of illness or death rate for severely ill patients. Even with two vaccines with EUA, and more on the horizon, it is likely that the SARS-CoV-2 virus and COVID-19 will persist and may become endemic. As such, vulnerable individuals will still get infected and may die if new anti-viral drugs are not developed soon. The primary aim of this proposal is to synthesize two different types of branched glycopolymers as potential broad spectrum anti-viral (BSAV) drugs. Our second major aim seeks to assess the glycopolymers for anti-viral activity against SARS-CoV-2 and HIV-1, both of which are responsible for current, significant pandemics affecting millions of people around the world. SARS-CoV-2 and HIV-1, along with many other viruses, share the ability to hijack cell surface heparan sulfate proteoglycans (HSPGs) as receptors in the early-stage binding/infection process. This is accomplished through electrostatic interactions between the viral surface glycoproteins, Spike (S, SARS-CoV-2) and gp120 (HIV-1). The glycopolymers will be designed to have polyanionic charges complementary to the polybasic regions of S and gp120. Using the two different classes of glycopolymers will allow for a more rapid assessment of which specific architectural features are most critical to yield the desired anti-viral effect. This will be accomplished using a rapid iterative design build test process where the glycopolymers are built in parallel, then assessed for anti-viral activities using first an ELISA (Enzyme- Linked Immunosorbent Assay) to evaluate viral protein binding and provide a “go/no go” decision. If positive binding is observed, then higher level bioassays will be used to assess quantitative binding (Kd) information, live cell anti-viral assays to provide IC50 (inhibitory concentration for 50% reduction in infection) values, and cytotoxicity evaluation. Computational methods will also be used to ascertain the most critical structural features present in the binding interactions (location, number of contact points, etc.). Evaluation of the comprehensive biological/structural results will inform further iterations of glycopolymer designs. Successful completion of this project has the potential to yield a new class of BSAV. This is crucial for fighting not only the current pandemics caused by both SARS-CoV-2 and HIV-1, but could also provide relief for future viruses not yet emerged.

项目总结/摘要 当前的COVID-19大流行已导致全球数百万人感染，200多万人死亡 自2019年12月中国武汉出现SARS-CoV-2以来，这一流行病揭示了一个重大的 在通过使用抗病毒药物尽量减少感染者的发病率和死亡率方面的治疗差距 毒品目前，只有remdesivir获得了FDA的紧急使用授权（EUA），但需要 IV给药5-10天，费用很高，并且没有显示出显著减少的持续时间。 严重病人的患病率或死亡率。即使有两种疫苗与EUA，并在地平线上更多，它是 SARS-CoV-2病毒和COVID-19可能会持续存在，并可能成为地方性流行病。因此，脆弱 如果不尽快研制出新的抗病毒药物，个人仍将受到感染，并可能死亡。 本论文的主要目的是合成两种不同类型的支链糖基共聚物， 广谱抗病毒（BSAV）药物。我们的第二个主要目标是评估用于抗病毒的糖聚合物 针对SARS-CoV-2和HIV-1的活动，这两种病毒都是造成当前重大流行病的原因 影响着全世界数百万人SARS-CoV-2和HIV-1，沿着许多其他病毒， 在早期阶段劫持细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）作为受体的能力 结合/感染过程。这是通过病毒表面之间的静电相互作用来实现的 糖蛋白，Spike（S，SARS-CoV-2）和gp 120（HIV-1）。糖共聚物将被设计为具有 多阴离子电荷与S和gp 120的多碱区域互补。使用两个不同的类， 糖聚合物将允许更快速地评估哪些特定的结构特征对 产生所需的抗病毒效果。这将使用快速迭代设计构建测试过程来完成 其中平行构建糖共聚物，然后首先使用ELISA（酶联免疫吸附法）评估抗病毒活性， 连接的免疫吸附测定）以评价病毒蛋白结合并提供“进行/不进行”决定。如果呈阳性 如果观察到结合，则将使用更高水平的生物测定来评估实时定量结合（Kd）信息 细胞抗病毒试验，提供IC 50（感染减少50%的抑制浓度）值，和 细胞毒性评价。计算方法也将用于确定最关键的结构特征 存在于结合相互作用（位置、接触点的数量等）中。综合评价 生物/结构结果将为糖聚合物设计的进一步迭代提供信息。 该项目的成功完成有可能产生一种新的BSAV。这对于战斗至关重要 这不仅是目前由SARS-CoV-2和HIV-1引起的流行病，而且还可以为未来的流行病提供缓解。 病毒尚未出现。