Protein Assembly Modulation: A New Approach to Amyotrophic Lateral Sclerosis (ALS) Therapeutics

作者：Shao Feng Yu, Kumar Paulvannan, Dennis Solas, Anuradha F. Lingappa, Ana Raquel Moreira, Shriya Sahu, Maya Michon, Amanda Macieik, Danielle Goldsmith, Nicholas DeYarman, Suguna Mallesh, M. Dharma Prasad, Claudia Maios, Kai Ruan, Giulio Srubek Tomassy, Elizabeth H. Jensen, Emma McGuirk, Verian Bader, Andreas Mueller-Schiffmann, Jonathan C. Reed, Jaisri R. Lingappa, Vinod Asundi, Shi Hong, Steve Jacobsen, Nicholas J. Brandon, Lyle W. Ostrow, Tom Lloyd, J. Alex Parker, Kim A. Staats, Justin K. Ichida, James C. Dodge, Debendranath Dey, Carsten Korth, Suganya Selvarajah, Vishwanath R. Lingappa, Jeffrey Rosenfeld · 发表于：Journal of Experimental Neurology · 年份：2024 · DOI：10.33696/neurol.5.103 · 被引用次数：6 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Biochemical and Molecular Research

Amyotrophic Lateral Sclerosis (ALS) is a devastating and progressive neurodegenerative disease with a complex, multifactorial pathophysiology, culminating in death of motor neurons. We introduce a new mechanism of ALS pathogenesis via study of a novel drug-like small molecule series that targets a subset of protein disulfide isomerase (PDI) within a previously largely unappreciated transient and energy-dependent multi-protein complex enriched for proteins of the ALS interactome. This drug, found by a novel phenotypic screen, has activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. The hit compound was initially identified as a modulator of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity against infectious HIV in cell culture. Its advancement for ALS-therapeutics, subsequent separation of activity against HIV and ALS into separate chemical subseries through structure-activity-relationship (SAR) optimization, and identification of the drug target by affinity chromatography as shown here, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.