Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2

Neil D Theise; Anthony R Arment; Dimple Chakravarty; John M H Gregg; Ira M Jacobson; Kie Hoon Jung; Sujit S Nair; Ashutosh K Tewari; Archie W Thurston; John Van Drie; Jonna B Westover

doi:10.1080/15384101.2020.1859752

Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2

Cell Cycle. 2020 Dec;19(24):3632-3638. doi: 10.1080/15384101.2020.1859752. Epub 2020 Dec 11.

Authors

Affiliations

¹ Department of Pathology, New York University-Grossman School of Medicine , New York, NY, USA.
² Palisades Therapeutics/Pop Test Oncology LLC , Cliffside Park, NJ, USA.
³ Department of Biology, Central State University , Wilberforce, OH, USA.
⁴ Department of Urology and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA.
⁵ Department of Medicine, New York University-Grossman School of Medicine , New York, NY, USA.
⁶ Department of Animal, Dairy, and Veterinary Sciences, Utah State University , Logan, UT, USA.
⁷ ADME Solutions, Inc , San Diego, CA, USA.
⁸ Van Drie Research , North Andover, MA, USA.

Abstract

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.

Keywords: Androgen receptor; COVID-19; Glucocorticoid antagonist; SARS-CoV-2; Therapeutic.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alveolar Epithelial Cells / drug effects
Alveolar Epithelial Cells / virology
Angiotensin-Converting Enzyme 2 / metabolism
Antiviral Agents / pharmacology*
Antiviral Agents / therapeutic use
COVID-19 Drug Treatment*
Cell Line
Disease Progression
Down-Regulation
Glucocorticoids / antagonists & inhibitors
Glucocorticoids / metabolism
Humans
Hydrocortisone / antagonists & inhibitors
Immunologic Factors / pharmacology
Immunologic Factors / therapeutic use
Middle East Respiratory Syndrome Coronavirus / drug effects
Receptors, Androgen / metabolism*
Receptors, Glucocorticoid / agonists
Receptors, Glucocorticoid / metabolism*
SARS-CoV-2 / drug effects*
Serine Endopeptidases / metabolism

Substances

Antiviral Agents
Glucocorticoids
Immunologic Factors
Receptors, Androgen
Receptors, Glucocorticoid
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human
Hydrocortisone

Grants and funding

Funded Studies: MERS related experiments were funded by NIH/NIAID. NIH/NIAID designed the study and performed data collection and analysis. Palisades Therapeutics/Pop Test Oncology LLC paid for SARS-CoV-2 related experiments and participated in study design, decision to publish, and preparation of the manuscript.