Optimization of Arenavirus Antivirals

描述（由申请方提供）：7种不同的沙粒病毒与人类沙粒病毒出血热（AVHF）相关，病死率高达30%。人感染沙粒病毒通常通过接触受感染啮齿动物排泄物污染的材料发生，尽管在临床环境中经常发生直接人传人。除登革热外，由旧大陆沙粒病毒拉沙感染引起的AVHF对人类的影响是所有病毒性出血热中最大的。据估计，每年在非洲造成30多万人感染， 15-20%的住院患者死亡，而幸存者往往遭受永久性后遗症。在阿根廷出血热（AHF）中也观察到了类似的结果，AHF是由新世界沙粒病毒朱宁感染引起的，已经开发了预防性疫苗。然而，目前还没有针对拉沙病毒或已知感染人类的其他六种沙粒病毒的疫苗，并且不太可能开发出有效对抗当前或新出现的沙粒病毒的广谱疫苗。唯一可用的抗病毒药物利巴韦林在治疗严重的沙粒病毒病方面取得了混合成功，并且与显著的毒性相关。鉴于缺乏 有效的治疗方法和药物，与感染有关的高死亡率，人畜共患和人传人的可能性，地理移植的可能性，以及由于大量的沙粒病毒可以在细胞培养中繁殖并作为气溶胶传播，五种引起严重VHF的沙粒病毒被认为是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。在此，我们提出了一个先导化学系列的I期药物化学优化，用于通过在各种BSL 2假型和活病毒研究中测定活性，并在BSL 4感染性拉沙病毒体外研究中进行最终确认，开发广谱沙粒病毒抗病毒药物。

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.