Article ; Online: Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.
Proceedings of the National Academy of Sciences of the United States of America
2020 Volume 117, Issue 39, Page(s) 24285–24293
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 ...
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. |
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MeSH term(s) | Humans ; Hydrogen Bonding ; Ligands ; Muscular Dystrophy, Duchenne/drug therapy ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/metabolism ; Pregnadienediols/administration & dosage ; Pregnadienediols/chemistry ; Protein Binding ; Receptors, Glucocorticoid/chemistry ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism |
Chemical Substances | Ligands ; Pregnadienediols ; Receptors, Glucocorticoid ; VBP15 compound |
Keywords | covid19 |
Language | English |
Publishing date | 2020-09-11 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
ZDB-ID | 209104-5 |
ISSN | 1091-6490 ; 0027-8424 |
ISSN (online) | 1091-6490 |
ISSN | 0027-8424 |
DOI | 10.1073/pnas.2006890117 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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