NAD-Restoring Compounds for Misfolded Protein Neurotoxicity
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Solution Overview
Problem
Current treatments for protein misfolding neurodegenerative diseases (PMNDs) only alleviate symptoms and do not slow down the progression of the underlying pathogenic mechanisms or halt neuronal loss, lacking disease-modifying therapies.
Innovation Solution
Administering compounds that interfere with NAD metabolism by inhibiting NAD consumption or increasing NAD synthesis to protect neurons from misfolded protein toxicity, using novel chemical structures to address the fundamental mechanisms of neurotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current treatments are used for PMNDs, then symptom alleviation is achieved, but disease progression is not slowed and neuronal loss is not halted
Solution Approach 1:
The patent extracts and targets the specific pathological mechanism of NAD depletion caused by misfolded protein toxicity. By isolating this key mechanism from the complex disease process, the invention develops compounds that specifically address NAD metabolism disruption, thereby achieving disease modification rather than just symptom management
Solution Approach 2:
The patent introduces NAD metabolism as an intermediary target between misfolded proteins and neuronal death. The compounds act as mediators that restore NAD levels, thereby interrupting the pathological cascade from protein misfolding to neuronal loss without directly targeting the misfolded proteins themselves
2Reliability
If NAD consumption is inhibited or NAD synthesis is increased, then neuronal protection from misfolded protein toxicity is achieved, but the complexity of the treatment mechanism increases
Solution Approach 1:
The patent changes the metabolic parameter of NAD levels in neurons affected by misfolded proteins. By developing compounds that specifically increase NAD synthesis or decrease NAD consumption, the invention restores the depleted NAD parameter without requiring complex multi-target mechanisms
Solution Approach 2:
The patent converts the harmful NAD depletion caused by misfolded proteins into a beneficial therapeutic target. By identifying NAD metabolism disruption as the cause of neuronal death, the invention develops compounds that restore NAD levels, thereby turning the pathological mechanism into a treatable condition
Data Source
AI summary
Compounds described herein may be used for the treatment of neurodegenerative diseases linked to protein misfolding, including prion diseases, Alzheimer's disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and also other neurodegenerative, degenerative, metabolic and ischemic conditions. Indeed, NAD metabolism impairment is also a critical feature in brain ischemia/reperfusion injury, Wallerian degeneration, kidney failure, multiple sclerosis, aging, and metabolic disorders such as diabetes mellitus. Therapies that elevate or stabilize NAD levels may thus have broad potential for treating many severely debilitating neurological and metabolic conditions. Evidence is provided herein with compounds from 8 lead series for NAD restoring properties and for therapeutic efficacy in cellular and/or animal models of prion disease, PD and ALS.