Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment

• Type of Material: Article
• Authors: Xu Liu, Emory University; Yashuo Wang, Emory University; Jennifer S Gutierrez, Emory University; Jesse M Damsker, ReveraGen Biopharma LLC; Kanneboyina Nagaraju, ReveraGen Biopharma LLC; Eric P Hoffman, ReveraGen Biopharma LLC; Eric Ortlund, Emory University
• Language: English
• Date: 2020-09-29
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: © 2020. Published under the PNAS license.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2006890117
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 117
• Issue: 39
• Start Page: 24285
• End Page: 24293
• Grant/Funding Information: These studies were supported by a W. M. Keck Foundation Medical Research Grant, ReveraGen Biopharma (Rockville, MD), and partially supported by the NIH (R01DK115213 to E.A.O.) X.L. was supported by an American Heart Association postdoctoral fellowship (17POST33660110)
• Keywords: ANTAGONISTS; MECHANISMS; STEROID-RECEPTORS; Science & Technology; PREDNISONE; glucocorticoid receptor; Multidisciplinary Sciences; NUCLEAR RECEPTOR; Science & Technology - Other Topics; PARTIAL AGONISTS; molecular dynamics; nuclear receptor; PLASTICITY; ACTIVATION; dissociative agonist; allostery; BINDING DOMAIN; EVOLUTION

Abstract

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.