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: 10333201
• 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/10333201
• 关键词: 2019-nCoV; Affect; Affinity; Alkynes; Antiviral Agents; Architecture; Azides; Binding; Binding Proteins; Biological; Biological Assay; Businesses; COVID-19; COVID-19 pandemic; Carbohydrates; Cell Line; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Charge; China; Computing Methodologies; Death Rate; Dendrimers; Development; Disease; 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; Individual; Infection; Lead; Length; Life; Link; Location; Luciferases; Measures; Membrane Glycoproteins; Methods; Morbidity - disease rate; Outcome; Oximes; Patients; Polymers; Porphyrins; Positron-Emission Tomography; Process; Proteins; Recording of previous events; Schools; Structure; Sulfate; Sulfur; Testing; Time; Vaccines; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Work; Zoonoses; base; copolymer; cost; cross reactivity; cycloaddition; cytotoxicity; design; electron energy; fighting; illness length; improved; inhibitor/antagonist; innovation; iterative design; molecular dynamics; monomer; mortality; novel; pandemic disease; pathogen; prevent; receptor; remdesivir; 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.

项目摘要/摘要 目前的新冠肺炎疫情已导致全球数百万人感染，200多万人死亡 自从武汉出现SARS-CoV-2病毒以来，中国于2019年12月。这场大流行揭示了一个重要的 通过使用抗病毒药物将感染者的发病率和死亡率降至最低的能力方面的治疗差距 毒品。目前只有瑞德韦获得了FDA的紧急使用授权(EUA)，但需要 高成本地静脉注射5-10天，并且没有表现出明显的缩短 重病患者的患病或死亡率。即使有两种EUA疫苗，而且更多的疫苗即将问世，它也是 SARS-CoV-2病毒和新冠肺炎很可能会持续存在，并可能成为地方性流行病。因此，易受攻击 如果不尽快开发新的抗病毒药物，个人仍将受到感染，并可能死亡。 这项建议的主要目的是合成两种不同类型的支链糖共聚物作为潜在的 广谱抗病毒(BSAV)药物。我们的第二个主要目标是评估糖共聚物的抗病毒作用。 抗击SARS-CoV-2和HIV-1的活动，这两种病毒都是当前重大流行病的原因 影响着世界各地数百万人。SARS-CoV-2和HIV-1以及许多其他病毒一样， 早期劫持细胞表面硫酸乙酰肝素蛋白多糖(HSPGs)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实现的 糖蛋白、斯派克(S，SARS-CoV-2)和gp120(艾滋病毒-1)。这种糖共聚物将被设计成具有 与S和gp120多碱区互补的多阴离子电荷。使用两个不同的类 糖共聚物将允许更快地评估哪些特定的建筑特征对 产生想要的抗病毒效果。这将使用快速迭代的设计构建测试过程来完成 其中糖共聚物是平行构建的，然后首先使用酶联免疫吸附试验(酶- 链接免疫吸附试验)，以评估病毒蛋白结合，并提供“去/不去”的决定。如果是肯定的 观察结合，然后使用更高水平的生物测定来评估定量结合(KD)信息，LIVE 细胞抗病毒检测，以提供IC50(感染减少50%的抑制浓度)值，以及 细胞毒性评价。还将使用计算方法来确定最关键的结构特征 存在于结合相互作用中(位置、接触点数量等)。综合考评 生物/结构结果将为糖共聚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个新的BSAV类别。这对战斗是至关重要的 不仅是目前由SARS-CoV-2和HIV-1引起的大流行，而且还可以为未来提供缓解 病毒还没有出现。