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, 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

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.

Conflict of interest statement

Neil D. Theise is Lead Scientist for Palisades Therapeutics/Pop Test Oncology LLC. John M. H. Gregg is Chief Operating Officer for Palisades Therapeutics/Pop Test Oncology LLC and has an equity interest in BalinBac Therapeutics, Inc. Anthony R. Arment, Ira M. Jacobson, Archie W. Thurston, Jr., and John Van Drie are consultants to Palisades Therapeutics/Pop Test Oncology LLC. Ira M. Jacobson has also consulted for, and received research support from, Gilead Sciences.

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