Loading

Original Research Open Access
Volume 5 | Issue 4 | DOI: https://doi.org/10.33696/Neurol.5.103

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

  • 1Prosetta Biosciences, Inc. 670 5th St San Francisco, CA 94107, USA
  • 2University of Montreal, Quebec, Canada
  • 3Current address Department of Neurology, Division of Biological Sciences, The University of Chicago, Chicago, IL, 60637, USA
  • 4Biogen, Cambridge, MA 02142, USA
  • 5Sanofi, Genomic Medicine Unit, Waltham, MA 02451, USA
  • 6Sanofi, Framingham, MA 01701, USA
  • 7Department of Neuropathology, University of Dusseldorf, Germany
  • 8University of Washington, Seattle 98109, USA
  • 9Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA
  • 10Temple University, Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
  • 11Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
  • 12University of Southern California, Los Angeles, CA 90033, USA
  • 13Department of Physiology, University of California, San Francisco, CA 94116, USA
  • 14Department of Neurology, Loma Linda Medical Center, Loma Linda CA 92354, USA
+ Affiliations - Affiliations

Corresponding Author

Vishwanath R. Lingappa, vlingappa@prosetta.com

Received Date: November 02, 2024

Accepted Date: November 20, 2024

Abstract

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.

Keywords

Affinity chromatography, Allostery, Molecular neuroscience, Neuro-degeneration, Phenotypic screen, Photocrosslinking, Protein assembly, Small molecule drug discovery, Structure activity relationship, Translational neuroscience

Author Information X