The heat shock protein 90 inhibitor RGRN-305 attenuates SARS-CoV-2 spike protein-induced inflammation in vitro but lacks effectiveness as COVID-19 treatment in mice.

The inhibition of heat shock protein 90 (HSP90), a molecular chaperone, has been proposed to be a potential novel treatment strategy for Coronavirus disease 2019 (COVID-19). In contrast to other studies, our data demonstrated that RGRN-305, a HSP90 inhibitor, exacerbated the cytopathic effect and did not reduce the viral shedding in VeroE6-hTMPRSS2 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Likewise in a murine model of SARS-CoV-2, transgenic mice treated orally with RGRN-305 exhibited reduced survival by the end of the experiment (day 12) as 14% (1/7) survived compared to 63% (5/8) of those treated with drug-vehicle. Animal weight was not reduced by the RGRN-305 treatment. Interestingly, we demonstrated that inhibition of HSP90 by RGRN-305 significantly dampened the inflammatory response induced by SARS-CoV-2 spike protein in human macrophage-like cells (U937) and human lung epithelial cells (A549). Measured by quantitative real-time PCR, the mRNA expression of the proinflammatory cytokines TNF, IL1B and IL6 were significantly reduced. Together, these data suggest that HSP90 inhibition by RGRN-305 exacerbates the SARS-CoV-2 infection in vitro and reduces the survival of mice infected with SARS-CoV-2, but exhibits strong anti-inflammatory properties. This data shows that while RGRN-305 may be helpful in a 'cytokine storm', it has no beneficial impact on viral replication or survival in animals as a monotherapy. Further animal studies with HSP90 inhibitors in combination with an anti-viral drug may provide additional insights into its utility in viral infections and whether HSP90 inhibition may continue to be a potential treatment strategy for COVID-19 disease.