[LIVE WEBINAR] Most central nervous system drugs target individual proteins to block disease triggers. This approach has produced limited progress against neurodegenerative diseases including ALS, Parkinson's Disease, and Alzheimer's Disease, because it is insufficient: return to full health requires restoration of homeostasis, the balance that is lost in disease. Often that happens by virtue of restorative feedback loops that are activated once disease triggers are blocked. Sometimes however, like the “colored wheel of doom” on your computer when the operating system is frozen, a reboot is required to restore homeostasis. This involves targeting the right allosteric sites on the particular multi-protein complex that governs the lost cellular function. Viruses have used natural selection over deep evolutionary time to identify these allosteric sites. At Prosetta, we have figured out how to use the viruses as “trufflehounds” to reveal small molecules that modulate those allosteric sites in the manner needed.
This live webinar features Vishwanath R. Lingappa, MD, PhD (CEO and CTO, Prosetta Biosciences; Emeritus Professor of Physiology and Medicine, University of California, San Francisco) for a discussion of assembly modulation as a drug discovery strategy. Dr. Lingappa will describe how Prosetta uses viruses as biological probes to identify druggable allosteric sites on protein assembly machines, and how this approach has produced small molecules with therapeutic activity across multiple CNS indications.
The session will cover the biology of host-catalyzed protein assembly, the cell-free protein synthesis and assembly (CFPSA) screening platform, and translational data from cellular and animal models of neurodegeneration. Dr. Lingappa will respond to attendee questions during a live Q&A following the presentation.
Discussion Topics
- The Limits of Conventional CNS Drug Discovery: Why protein-by-protein targeting falls short, especially for diseases of homeostasis, and the challenge of identifying the optimal allosteric site in multi-protein complexes containing hundreds of candidate sites.
- Assembly Modulation as a Therapeutic Strategy: The biology of host-catalyzed protein assembly, the existence of aberrant assembly machines in disease states, and the rationale for restoring homeostasis through allosteric site engagement.
- Viruses as Biological Probes: How CFPSA-based phenotypic screens across pathogenic viral families identified a diverse collection of small molecules with activity against host assembly machinery, some of which is shared with non-viral CNS disease.
- ALS Therapeutics: Restoration of TDP-43 homeostasis in patient-derived fibroblasts, iPSC-derived motor neurons, and transgenic worm, fly, and mouse models. Identification of a subset of PDI as the direct drug-binding protein. Development of a PBMC-based diagnostic biomarker.
- Parkinson's Disease Therapeutics: Protection of dopaminergic neurons from rotenone- and dopamine-induced toxicity in primary rat neurons and LUHMES cells. Identification of a subset of mTOR as the direct drug-binding protein.
- Alzheimer's Disease Therapeutics: Oxidized MIF (oxMIF) as a drug target. Inhibition of HSV-1 replication and reduction of tau phosphorylation by the PAV-174 lead series.
- Translational Outlook: Rodent PK/tox profile of the ALS lead chemotype, diagnostic applications enabling early detection of CNS disease, and the path toward IND filing.
- Live Q&A: Attendees will have the opportunity to submit questions directly to Dr. Lingappa during the session.
Who Should Attend
This session is intended for medicinal chemists, neuroscientists, biologists, and R&D leaders working in CNS drug discovery, neurodegeneration, and small-molecule therapeutics. Biotech executives and investors evaluating platform approaches to neurodegenerative disease will also find the content relevant.
