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

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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.