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.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Receptors, Androgen/metabolism , Receptors, Glucocorticoid/metabolism , SARS-CoV-2/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , 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, Glucocorticoid/agonists , Serine Endopeptidases/metabolismABSTRACT
The recent revolution in cryo-EM has produced an explosion of structures at near-atomic or better resolution. This has allowed cryo-EM structures to provide visualization of bound small-molecule ligands in the macromolecules, and these new structures have provided unprecedented insights into the molecular mechanisms of complex biochemical processes. They have also had a profound impact on drug discovery, defining the binding modes and mechanisms of action of well-known drugs as well as driving the design and development of new compounds. This review will summarize and highlight some of these structures. Most excitingly, the latest cryo-EM technology has produced structures at 1.2 Å resolution, further solidifying cryo-EM as a powerful tool for drug discovery. Therefore, cryo-EM will play an ever-increasing role in drug discovery in the coming years.