Optimization of Arenavirus Antivirals

沙粒病毒抗病毒药物的优化

• 批准号: 8802859
• 负责人: Ken J McCormack
• 金额: $ 30万
• 依托单位: ARISAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8802859
• 关键词: Aerosols; Africa; Antiviral Agents; Area; Arenavirus; Biological Assay; Biological Warfare; Bolivian Hemorrhagic Fever Virus; Caco-2 Cells; Case Fatality Rates; Categories; Cell Culture Techniques; Chemicals; Chemistry; Clinical; Complex; Cytochrome P450; Dengue; Development; Disease; Excretory function; Exhibits; Family; Generations; Glycoproteins; Health; Hour; Housing; Human; In Vitro; Infection; Junin virus; Lassa virus; Lead; Life; Liver Microsomes; Mediating; Membrane Fusion; Namibia; National Institute of Allergy and Infectious Disease; North America; Old World Arenaviruses; Oral Administration; Outcome; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Property; Prophylactic treatment; Research; Ribavirin; Risk; Route; Series; Small Business Innovation Research Grant; Solubility; South America; Staging; Surface; Survivors; Tacaribe Complex Viruses; Tacaribe virus; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transplantation; United States National Institutes of Health; Vaccines; Vero Cells; Viral; Viral Hemorrhagic Fevers; Virus; aqueous; base; cytochrome c; cytotoxicity; effective therapy; improved; indexing; infected vector rodent; inhibitor/antagonist; innovation; lipophilicity; meetings; mortality; novel; pathogen; prophylactic; research study; success; transmission process

DESCRIPTION (provided by applicant): Seven distinct arenavirus species have been associated with arenaviral hemorrhagic fevers (AVHF) in humans, with case-fatality rates as high as 30%. Human infection with arenaviruses typically occurs through contact with materials contaminated with the excretions of an infected rodent although direct human-to-human transmission often occurs in clinical settings. AVHF resulting from infection with the Old World arenavirus Lassa, with the exception of Dengue Fever, has the highest human impact of any of the viral hemorrhagic fevers. It is estimated to cause over 300,000 annual infections in Africa, of which 15-20% of hospitalized patients die while survivors often suffer permanent sequelae. Similar outcomes are observed with Argentine hemorrhagic fever (AHF), caused by infection with the New World arenavirus Junin for which a prophylactic vaccine has been developed. However, no vaccines are available for Lassa or the six other arenaviruses known to infect humans and broad-spectrum vaccines effective against current or emerging arenaviruses are unlikely to be developed. The only available antiviral, ribavirin, has had mixed success in treating severe arenaviral disease and it is associated with significant toxicities. Given the lack of effective treatments and prophylactics, the high mortality rate associated with infection, the potential for both zoonotic and human-to-human transmission, the potential for geographical transplantation, and because large quantities can be propagated in cell culture and transmitted as aerosols, five arenaviruses eliciting severe VHF have been recognized as Category A pathogens; the development of broad spectrum antivirals for the treatment and prophylaxis of VHF is an NIAID priority. Here we propose phase I medicinal chemistry optimization of a lead chemical series for the development of broad spectrum arenavirus antivirals through determination of activity in a variety of BSL2 pseudotype and live virus studies with final confirmation in BSL4 infectious Lassa virus in vitro studies.

描述(由申请人提供)：七种不同的阿拉伯病毒与人类无病毒出血热(AVHF)有关，病死率高达30%。人类感染ArenaVirus病毒通常是通过接触受感染啮齿动物排泄物污染的材料发生的，尽管在临床环境中经常发生人与人之间的直接传播。除登革热外，由东半球冠状病毒Lassa感染引起的AVHF对人类的影响是所有病毒性出血热中最高的。据估计，它每年在非洲造成30多万人感染， 其中15%-20%的住院患者死亡，而幸存者往往遭受永久性后遗症。阿根廷出血热(AHF)也有类似的结果，它是由感染新大陆新冠病毒Junin引起的，已经为其开发了预防性疫苗。然而，目前还没有针对Lassa或其他六种已知可感染人类的Arena病毒的疫苗，也不太可能开发出有效对抗现有或新兴Arena病毒的广谱疫苗。唯一可用的抗病毒药物利巴韦林在治疗严重的阿拉伯病毒疾病方面取得了好坏参半的结果，而且它与严重的毒性有关。考虑到缺乏 在有效的治疗和预防药物中，与感染相关的高死亡率、人畜共患病和人传人的可能性、地理移植的可能性，以及由于大量病毒可以在细胞培养中繁殖并以气雾剂传播，引起严重的VHF的五种ARENA病毒已被确认为A类病原体；开发用于治疗和预防VHF的广谱抗病毒药物是NIAID的优先事项。在这里，我们提出了第一阶段药物化学优化，用于开发广谱ArenaVirus抗病毒药物，方法是测定各种BSL2假型的活性，并进行活病毒研究，最终证实BSL4感染性拉萨病毒在体外研究中的有效性。