HSP90 paralog selective small molecules as anti-old-world alpha-viral therapeutic leads.

COVID-19疫情凸显了新兴传染病的影响和全球社会经济影响。 诸如基孔肯雅病毒（CHIKV）的甲病毒已经与许多节肢动物传播的病毒一起沿着重新出现 （虫媒病毒），这些病毒继续对全球人类健康构成重大威胁，特别是最近 向非地方病地区传播。CHIKV属于披膜病毒科， 白纹伊蚊和埃及伊蚊传播的由CHIKV热疾病引起的仰卧姿势和 病毒可分为三个不同的谱系， 地理起源CHIKV感染引起高血清病毒载量，因此，高病毒血症也有助于 迅速蔓延。与其他甲病毒一样，CHIKV和相关病毒感染没有治疗方法。近几 在探索性研究中，我们已经鉴定了两种抑制CHIKV和相关甲病毒Mayaro病毒的抑制剂， （MAYV）。虽然先前的研究已经显示了HSP 90抑制剂的潜在作用，但与HSP 90抑制剂相关的主要局限性是： HSP 90抑制剂的进一步发展是泛HSP 90活性导致毒性。HSP 90家族包括： 4种不同的旁系同源物，两种胞质形式HSP 90 α（由HSP 90 AA 1编码），HSP 90 β（由HSP 90 AB 1编码） 基因），Grp 94，内质网驻留HSP 90（由HSP 90 B1编码）和线粒体Trap 1。而 泛热休克蛋白90活性提供了初步的见解，他们有许多临床责任。在我们的研究中，我们 将开发具有降低毒性和增强功效的HSP 90 β特异性抑制剂，作为宿主定向抗- 甲病毒治疗铅。我们期望将一个或多个支架从命中移动到选择性指数>200的铅 并确定作用机制（MOA）。我们将共同填补这一领域的一个关键空白。

COVID-19 pandemic highlights the impact of emerging infectious diseases and the global socioeconomic impact. Alphaviruses such as the chikungunya virus (CHIKV) has re-emerged along with many arthropod-borne viruses (arboviruses) and these viruses continue to pose a significant threat to global human health especially with recent vector expansion into non-endemic regions. CHIKV belongs to the Togaviridae family and is transmitted mainly by Aedes albopictus and Aedes aegypti mosquitose. The bent-up posture caused by CHIKV fever disease and the virus can be classified into three different lineages with distinct genotypes corresponding to their respective geographical origins. CHIKV infections cause high serum viral loads, and therefore, high viremia also contributes to rapid spread. Like other alphaviruses, there are no treatments for CHIKV and related viral infections. In recent exploratory studies, we have identified two inhibitors that inhibit CHIKV and related alphavirus Mayaro virus (MAYV). While prior studies have shown a potential role for HSP90 inhibitors, a major limitation associated with further development of HSP90 inhibitors is that pan-HSP90 activity results in toxicity. HSP90 family consists of 4 different paralogs, two cytosolic forms HSP90α (encoded by HSP90AA1), HSP90β (encoded by HSP90AB1 gene), Grp94, an endoplasmic reticulum resident HSP90 (encoded by HSP90B1) and mitochondrial Trap1. While pan-HSP90 activity provides the initial insights, they have many clinical liabilities. In our proposed studies, we will develop HSP90β specific inhibitors with reduced toxicity and enhanced efficacy as a host-directed anti- alphavirus therapeutic lead. We expect to move one or more scaffolds from hit-to-lead with selectivity index >200 and determine the mechanism of action (MOA). Collectively, we will fill a critical gap in the field.