Unco Therapeutics LLC

Development of Allosteric Uncouplers as Therapeutics for Chronic Pain - Chronic Pain Is a Neurological Disease That Affects Millions Worldwide Every Year. Currently, Opioids Are the Only Effective Treatments for Moderate to Severe Pain, But They Come With Serious Life-threatening Side Effects and Are Highly Addictive. the Widespread Addiction to Opioids Has Created a Serious Public Health Crisis of Opioid Misuse. in 2021 Alone, Nearly 100,000 Americans Died of Opioid Overdose, and Thus, Effective and Safe Non-opioid Therapeutic Alternatives Are Highly Wanted. in Cancer-associated, Inflammatory, and Neuropathic Pain, Serine and Cysteine Proteases Are Secreted Into the Local Microenvironment, Which Stimulate the Protease-activated Receptor 2 (PAR2) in Sensory Neurons Causing Hyperexcitability of Nociceptors and Pain Sensation. as PAR2 Belongs to the Highly Druggable Superfamily of G Protein-coupled Receptors, the Receptor Has Been Considered a Promising Drug Target for Chronic Pain. However, PAR2 Has Turned Out Very Challenging to Effectively Antagonize Using Traditional Small Molecule and Peptide Strategies as Well as More Creative Solutions Including Pepducins and Antibodies. One of Challenges in Targeting PAR2 Relates to the Fact That Proteases Themselves Do Not Directly Activate PAR2 But Do So Indirectly via Proteolytic Cleavage of the PAR2 N-terminal Leading to Exposure of a Tethered Peptide Agonist That Irreversibly Activates the Receptor. as Traditional Antagonists Cannot Effectively Compete Off the Covalently Attached Peptide Agonist to Shut Down PAR2-MEDIATED Signaling, We Here Propose to Develop a New Class of Small Molecule Pharmaceuticals to Block Downstream Effects. These Compounds, Called Allosteric Uncouplers, Bind to the Intracellular G Protein-binding Site Within the Active Receptor Conformation, Instead of Competing With the Inaccessible Orthosteric Binding Site. Since the PAR2–G Protein Interaction Is Transient, Allosteric Uncouplers Can Compete for This Site to Shut Down G Protein Signaling and Nociception Independent of the Protease-mediated Exposure of the Tethered PAR2 Peptide Agonist. in Preliminary Work, We Used Computational/ai-based Screening and Cell-based Pharmacological Characterization to Identify Several Small Molecule Series. the Antagonistic Uncoupler Function of Some of These Compounds Has Been Validated in Ex Vivo and in Vivo Pain Models. However, the Compounds Originate From Commercially Available Sources, Their Potencies Are Low, and Some Contain Suboptimal Chemical Features Associated With Toxicity Risks, Low CNS Exposure, and Metabolic Instability. Thus, the Main Goal of This STTR Award Is to Optimize Current Allosteric Uncoupler Series Based on Thiazolidines, Naphthyl-diamine, and Pyrazolopyramidines Scaffolds to Produce Novel, Potent and Selective Drug-like Compounds to Block the PAR2–G Protein Interaction, and Which Can Be Protected via Patenting. Such Allosteric Uncouplers Have a Strong Potential to Be Effective and Safe Analgesic Alternatives to Opioids.