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A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2

Savannah M. Rocha, Anna C. Fagre, Amanda S. Latham, Katriana A. Popichak, Casey P. McDermott, Clinton C. Dawson, Jason E. Cummings, Juliette Lewis, Philip Reigan, Tawfik A. Aboellail, Rebekah C. Kading, View ORCID ProfileTony Schountz, Neil D. Theise, Richard A. Slayden, View ORCID ProfileRonald B. Tjalkens
doi: https://doi.org/10.1101/2021.02.20.432110
Savannah M. Rocha
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Anna C. Fagre
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Amanda S. Latham
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Katriana A. Popichak
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Casey P. McDermott
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Clinton C. Dawson
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Jason E. Cummings
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Juliette Lewis
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Philip Reigan
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Denver, CO, USA
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Tawfik A. Aboellail
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Rebekah C. Kading
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Tony Schountz
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Neil D. Theise
4Department of Pathology, New York University-Grossman School of Medicine, New York, NY
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Richard A. Slayden
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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  • For correspondence: ron.tjalkens@colostate.edu richard.slayden@colostate.edu
Ronald B. Tjalkens
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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  • ORCID record for Ronald B. Tjalkens
  • For correspondence: ron.tjalkens@colostate.edu richard.slayden@colostate.edu
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Abstract

Since its initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID19, has spread worldwide and despite significant research efforts, treatment options remain limited. Replication of SARS-CoV-2 in lung is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses triggered, in part, by heightened production of interleukin-6 (IL-6) that recruits lymphocytes to the site of infection that amplify tissue injury. Antagonists of the glucocorticoid and androgen receptors have shown promise in experimental models of COVID19 and in clinical studies, because cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2), are transcriptionally regulated by these receptors. We therefore postulated that the glucocorticoid (GR) and androgen receptor (AR) antagonist, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID19. Animals were infected intranasally with 2.5 × 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/ 2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were then examined at days 3, 5 and 7 post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the initiation and progression of SARS-CoV-2 infection. Results of these studies indicated that oral administration of PT150 decreased replication of SARS-CoV-2 in lung, as well as expression of ACE2 and TMPRSS2 protein. Hypercellularity and inflammatory cell infiltration driven by macrophage responses were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular modeling suggested that PT150 binds to the co-activator interface of the ligand binding domain of both AR and GR and thereby acts as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR across multiple species permissive to SARS-CoV-2 infection revealed a high degree of sequence identity maintained across species, including human, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID19 across variants of SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 22, 2021.
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A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2
Savannah M. Rocha, Anna C. Fagre, Amanda S. Latham, Katriana A. Popichak, Casey P. McDermott, Clinton C. Dawson, Jason E. Cummings, Juliette Lewis, Philip Reigan, Tawfik A. Aboellail, Rebekah C. Kading, Tony Schountz, Neil D. Theise, Richard A. Slayden, Ronald B. Tjalkens
bioRxiv 2021.02.20.432110; doi: https://doi.org/10.1101/2021.02.20.432110
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A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2
Savannah M. Rocha, Anna C. Fagre, Amanda S. Latham, Katriana A. Popichak, Casey P. McDermott, Clinton C. Dawson, Jason E. Cummings, Juliette Lewis, Philip Reigan, Tawfik A. Aboellail, Rebekah C. Kading, Tony Schountz, Neil D. Theise, Richard A. Slayden, Ronald B. Tjalkens
bioRxiv 2021.02.20.432110; doi: https://doi.org/10.1101/2021.02.20.432110

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