The Structural and Biochemical Studies of the Mineralocorticoid Receptor Ligand Binding Domain Complexed with Vamorolone Open Access

Lee, Su-Wei (Spring 2022)

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Duchenne muscular dystrophy (DMD) is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle ultimately resulting in premature death in boys due to end-stage heart failure. Heart failure is often treated with drugs that lower blood volume and pressure, decreasing functional demand on the heart, such as mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone. Furthermore, the current standard of care for DMD, anti-inflammatory corticosteroids, alleviates DMD progression but drives adverse side effects such as bone mineral density loss and growth stunting through interactions with glucocorticoid receptors (GR). Through subtle modification to a steroidal backbone, vamorolone, a recently developed drug, appears to decrease muscle inflammation, stabilize muscle strength, and suppress cardiomyopathy without significant side effects due to its interactions with both MR and GR. Although the interaction between vamorolone and GR has been extensively studied, how vamorolone antagonizes MR remains poorly understood. In this study, we determined the crystal structure of MR LBD vamorolone complex and through biochemical studies identified that vamorolone could be acting as a potential passive antagonist. Our result sheds light to the possible similarities between vamorolone and known MR passive antagonists, spironolactone and eplerenone, guiding future studies to focus on the local conformational dynamics and coregulator binding patterns. Collectively, this work advances our understanding of vamorolone’s mechanism of action and efficacy of cardiac muscle protection.

Table of Contents

Chapter 1: Introduction 1

Chapter 2: Purifying MR LBD with various ligands                                                            6

Chapter 3: MR LBD-vamorolone structure via X-ray crystallography                                12

Chapter 4: Biophysical and biochemical assays with MR LBD                                            17

Chapter 5: Discussion and future directions                                                                         20

References      23

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