Protein Assembly Modulation: A New Approach to ALS Therapeutics

Yu, S. F.; Paulvannan, K.; Solas, D.; Lingappa, A. F.; Moreira, A. R.; Sahu, S.; Michon, M.; Goldsmith, D.; DeYarman, N.; Mallesh, S.; Prasad, M. D.; Maios, C.; Ruan, K.; Tomassy, G. S.; Jensen, E.; McGuirk, E.; Bader, V.; Meuller-Schiffmann, A.; Reed, J. C.; Lingappa, J. R.; Asundi, V.; Hong, S.; Jacobsen, S.; Ostrow, L.; Lloyd, T.; Parker, A. E.; Staats, K. A.; Ichida, J.; Dodge, J.; Dey, D.; Korth, C.; Selvarajah, S.; Lingappa, V. R.; Rosenfeld, J.

doi:10.1101/2023.07.24.550252

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bioRxiv · 10.1101/2023.07.24.550252

Protein Assembly Modulation: A New Approach to ALS Therapeutics

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have 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. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.

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Yu, S. F., Paulvannan, K., Solas, D., Lingappa, A. F., Moreira, A. R., Sahu, S., Michon, M., Goldsmith, D., DeYarman, N., Mallesh, S., Prasad, M. D., Maios, C., Ruan, K., Tomassy, G. S., Jensen, E., McGuirk, E., Bader, V., Meuller-Schiffmann, A., Reed, J. C., Lingappa, J. R., Asundi, V., Hong, S., Jacobsen, S., Ostrow, L., Lloyd, T., Parker, A. E., Staats, K. A., Ichida, J., Dodge, J., Dey, D., Korth, C., Selvarajah, S., Lingappa, V. R., Rosenfeld, J.. 2023-07-26. Protein Assembly Modulation: A New Approach to ALS Therapeutics. https://doi.org/10.1101/2023.07.24.550252

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