Novel Anti-Viral Agents for Treating Lassa Fever

用于治疗拉沙热的新型抗病毒药物

• 批准号: 6855134
• 负责人: PHILIP E THORPE
• 金额: $ 35.79万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855134
• 关键词: Lassa virus; antiviral agents; biomaterial development /preparation; biotechnology; cooperative study; disease /disorder model; drug screening /evaluation; electron microscopy; enzyme linked immunosorbent assay; guinea pigs; immunocytochemistry; immunologic substance development /preparation; monoclonal antibody; northern blottings; pharmacokinetics; phospholipids; virus diseases

DESCRIPTION (provided by applicant): Our goal is to develop new, broad-spectrum anti-viral agents for treating viral infections caused by hostile dissemination of viral pathogens. The new agents act by targeting normally-internal phospholipids (e.g. phosphatidylserine, PS) that become exposed on the surface of virally-infected cells. Exposure of these phospholipids on infected host cells appears to be necessary for viral maturation or egress. We have raised monoclonal antibodies to PS and other anionic phospholipids that block the spread of several viruses to uninfected cells in vitro, essentially completely. The viruses we have tested thus far include an arenavirus (Pichinde virus), a paramyxovirus (respiratory syncytial virus) and a herpes virus (cytomegalovirus). The phospholipids that they recognize have the same structure and cellular distribution in different mammalian species, simplifying the transition from experimental animals into humans. The antibodies are not toxic to mice, even when administered in high doses for prolonged periods of time. One of the antibodies has been converted into a human-mouse chimeric antibody (ch3G4) and is being produced in a GMP facility by a commercial partner in anticipation of human use. We propose to develop ch3G4 first for treating Lassa fever. Development studies will be conducted in a guinea pig model, which uses the arenavirus, Pichinde, to mimic Lassa fever in humans. The animal model will enable us to safely investigate the mechanism of the anti-viral effect and to establish basic efficacy, safety and pharmacokinetic parameters. Key findings will then be validated for Lassa fever virus itself and with other arenaviruses that cause hemorrhagic fevers in a BSL-4 containment facility at UTMB Center for Biodefense, Galveston. The information generated by these studies may also extend to other viruses that could be used for bioterrorism purposes.

描述（由申请人提供）：我们的目标是开发新的，广谱的抗病毒药物来治疗由病毒病原体敌对传播引起的病毒感染。新药物通过靶向正常内部磷脂（例如磷脂酰丝氨酸，PS），这些磷脂在病毒感染细胞的表面暴露。这些磷脂在感染宿主细胞上的暴露似乎对于病毒成熟或流出是必要的。我们已经提高了对PS和其他阴离子磷脂的单克隆抗体，这些抗体阻止了几种病毒在体外完全完全完全完全受感染细胞的传播。到目前为止，我们已经测试的病毒包括体育经瘤病毒（Pichinde病毒），帕托氏菌病毒（呼吸综合病毒）和疱疹病毒（巨细胞病毒）。他们识别的磷脂在不同的哺乳动物物种中具有相同的结构和细胞分布，从而简化了从实验动物向人类的过渡。即使长时间以高剂量给药，抗体也对小鼠无毒。其中一种抗体已转化为人鼠嵌合抗体（CH3G4），并由商业伙伴在GMP设施中生产，以期预期人类使用。我们建议首先开发CH3G4来治疗Lassa热。开发研究将以豚鼠模型进行，该豚鼠模型使用体育症病毒Pichinde模仿人类的Lassa热。动物模型将使我们能够安全地研究抗病毒作用的机制，并建立基本功效，安全性和药代动力学参数。然后，将在LASSA发烧病毒本身以及其他竞技病毒中验证关键发现，并在Galveston的UTMB Biodefense中心的BSL-4遏制设施中引起出血性发烧。这些研究产生的信息也可能扩展到可用于生物恐怖目的的其他病毒。