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.

Autor:	Ben Abdallah H; Department of Dermatology, Aarhus University Hospital, Aarhus N, Denmark., Marino G; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Idorn M; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., S Reinert L; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Bregnhøj A; Department of Dermatology, Aarhus University Hospital, Aarhus N, Denmark., Paludan SR; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Johansen C; Department of Dermatology, Aarhus University Hospital, Aarhus N, Denmark.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2024 Sep 26; Vol. 19 (9), pp. e0310915. Date of Electronic Publication: 2024 Sep 26 (Print Publication: 2024).
DOI:	10.1371/journal.pone.0310915
Abstrakt:	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. Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: H.B.A has received research grants from Aage Bangs Fund and participated in clinical trials sponsored by Galderma, Regranion and UCB. C.J. has served as a paid speaker for LEO Pharma, Eli Lilly and L’Oréal This does not alter our adherence to PLOS ONE policies on sharing data and materials. (Copyright: © 2024 Ben Abdallah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze:	MEDLINE
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