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.

项目概要/摘要 当前的 COVID-19 大流行已导致全球数百万人感染和超过 200 万人死亡 自 2019 年 12 月在中国武汉出现 SARS-CoV-2 以来，这场大流行揭示了重大的 通过使用抗病毒药物最大程度降低感染者发病率和死亡率的治疗差距 药物。目前只有瑞德西韦获得FDA紧急使用授权（EUA），但要求 静脉注射5-10天的成本很高，并且没有显示出显着缩短治疗时间 重症患者的患病率或死亡率。即使有两种带有 EUA 的疫苗，以及即将推出的更多疫苗，它仍然是 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，脆弱的 如果不尽快开发出新的抗病毒药物，人们仍然会被感染，甚至可能死亡。 该提案的主要目的是合成两种不同类型的支化糖聚合物作为潜在的 广谱抗病毒（BSAV）药物。我们的第二个主要目标是评估糖聚合物的抗病毒作用 针对 SARS-CoV-2 和 HIV-1 的活动，这两种病毒都是当前重大流行病的罪魁祸首 影响着全世界数百万人。 SARS-CoV-2 和 HIV-1 以及许多其他病毒具有相同的特征 早期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 gp120（HIV-1）。糖聚合物将被设计为具有 聚阴离子电荷与 S 和 gp120 的多元区域互补。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于 产生所需的抗病毒效果。这将通过快速迭代设计构建测试流程来完成 其中糖聚合物是并行构建的，然后首先使用 ELISA（酶- 联免疫吸附测定）来评估病毒蛋白结合并提供“进行/不进行”的决定。如果呈阳性 观察到结合，然后使用更高水平的生物测定来评估定量结合（Kd）信息，实时 细胞抗病毒检测可提供 IC50（感染减少 50% 的抑制浓度）值，以及 细胞毒性评价。计算方法还将用于确定最关键的结构特征 存在于结合相互作用中（位置、接触点的数量等）。综合评价 生物学/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新型 BSAV。这对战斗至关重要 不仅可以缓解当前由 SARS-CoV-2 和 HIV-1 引起的大流行，还可以缓解未来的疫情 病毒还没有出现。