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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.
- Source :
- PLoS ONE; 9/26/2024, Vol. 19 Issue 9, p1-13, 13p
- Publication Year :
- 2024
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- SARS-CoV-2
CORONAVIRUS disease treatment
COVID-19
VIRUS diseases
COVID-19 treatment
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 19
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 179947683
- Full Text :
- https://doi.org/10.1371/journal.pone.0310915