[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 screen when the operating system is frozen, a reboot is
required to restore homeostasis. This typically 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 critical 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 assembled a collection of assembly modulator small molecules and is simultaneously advancing a subset towards the clinic while using the drugs themselves as probes of the novel targets and mechanism of action for each of several 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 complex 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, and some of which have been advanced to disease-selectivity.
- 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 within a large multi-protein complex enriched in proteins of the ALS interactome. Development of a PBMC-based diagnostic biomarker allowing identification of ALS patients early, prior to serious disability.
- 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 within the Parkinson’s Disease protein interactome.
- 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.
