ANTI-FUSOGENIC ANTIVIRALS: DESIGN AND TESTING

抗融合抗病毒药物：设计和测试

• 批准号: 3489005
• 负责人: Jay F. Stearns
• 金额: $ 5万
• 依托单位: SERES LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1989-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3489005
• 关键词: antiviral agents; chemical binding; chemical structure function; computer simulation; drug design /synthesis /production; influenza; ligands; mass spectrometry; membrane fusion; microorganism hemagglutinin; nuclear magnetic resonance spectroscopy; plaque assay; receptor binding; virus antigen; virus protein; virus receptors

A recently developed computer algorithm, capable of defining the accessible surface of polypeptides, has revealed a possible binding site on the hemagglutinin (HA) envelope protein of influenza virus. The proximity of this site to the fusion peptide of HA makes it an attractive candidate as a target for arresting influenza by inhibiting virus membrane fusion. A variety of structures, complementary in shape and charge to this HA site, have been identified by computer docking experiments. Deoxycytidine, and adamantane skeletons provide the best fits for compounds which are readily synthesized. The proposal describes the acquisition of commercially available compounds and the synthesis of four new trial ligands as representatives of these structures to test the feasibility of preventing membrane fusion of influenza virus by binding to this HA site. Trial ligands that inhibit release of the fusion peptide from the HA trimer interface, and show in vitro inhibition of viral fusion, will be tested for antiviral activity by plaque assay. This Phase I feasibility study will provide a framework leading to the development of low dosage, safe anti- influenza therapeutics in Phase II. This work will also provide a new strategy for antiviral therapy.

最近开发的计算机算法，能够定义 多肽的可及表面揭示了可能的结合 位于流感病毒的血凝素（HA）包膜蛋白上。 该站点与HA融合肽的接近性使其成为 有吸引力的候选人作为逮捕流感的目标 抑制病毒膜融合。 多种结构， 对此HA地点的形状和费用互补，已经 通过计算机对接实验确定。 脱氧胞苷和 Adamantane骨骼为化合物提供了最佳拟合 容易合成。 该提案描述了收购 市售的化合物和四个新的合成 试验配体作为这些结构的代表测试 防止流感病毒膜融合的可行性 与此HA站点结合。 抑制释放的试验配体 来自HA三聚体界面的融合肽，并在体外显示 抑制病毒融合，将测试抗病毒活性 由斑块测定法。 这一阶段I可行性研究将提供 框架导致低剂量的发展，安全抗 第二阶段的流感疗法。 这项工作也将提供 抗病毒治疗的新策略。