Never in the history of the United States has the unmet medical need to develop novel, non-opioid therapeutics for chronic pain been more urgent than it is today. More than 65 million US adults suffer from chronic pain, resulting in almost $635 billion in annual healthcare costs. Despite their limited efficacy, and potential for addiction, tolerance, and impaired motor performance, opioids have become a mainstay for chronic pain management, resulting in an opioid epidemic that is ravaging communities throughout the US. Thus, there is an urgent need to develop novel, non-opioid therapies for chronic pain management. This application addresses this unmet medical need by leveraging our novel artificial intelligence (AI)-driven drug discovery platform to develop selective inhibitors of calpain-1 as novel non-opioid therapeutics for chronic pain. Studies in chronic neuropathic pain animal models have shown that nerve injury overactivates calpain-1, which downregulates K+ Cl- cotransporter activity, resulting in diminished synaptic inhibition and neuropathic pain. Prior work by our group has also shown that both pharmacological inhibition and whole body genetic knockout of calpain-1 attenuates chronic pain behaviors in mouse models of sickle cell disease (SCD). Importantly, the analgesic effect of calpain-1 inhibition did not induce tolerance side effects, suggesting the potential for calpain-1 inhibitors to be non-addictive. By applying our innovative artificial intelligence (AI)-driven drug discovery platform to screen a virtual chemical library, we identified four (4) novel calpain-1 inhibitors, and validated them for efficacy in biochemical assays. Here, we propose to progress our most potent hit compound to a lead compound that is calpain-1 selective, cysteine protease family selective, non-opioid, and CNS penetrant with efficacy demonstrated in at least 1 of 3 chronic pain animal models tested, including chronic sickle cell disease pain, chronic inflammatory pain, and chronic neuropathic pain. Three aims are proposed, including Aim 1: Synthesize ~100 analogs of our most potent hit compound, and characterize in vitro activity and selectivity. Success criteria: Top 20 cell-permeable, calpain-1 inhibitors, moderately selective against calpain-2, and highly selective against cathepsins and caspase-1, Aim 2: Evaluate ADME-Tox and PK profile of our top 20 calpain-1 inhibitors from Aim 1. Success criteria: Top 2 CNS-penetrant selective calpain-1 inhibitors with favorable in vivo PK profile, and Aim 3: Determine the efficacy and PK/PD relationship of our top calpain-1 inhibitor in 3 chronic pain animal models. Success: at least 40% reduction in mechanical hyperalgesia in at least 1 of the 3 chronic pain animal models tested. Successful completion of this Phase I will yield a novel CNS-penetrant, selective calpain-1inhibitor with efficacy demonstrated in at least 1 chronic pain animal model. Our overall product would be the first, oral, CNS acting, selective calpain-1 inhibitor for chronic pain. Importantly, our product would reduce opioid usage in chronic pain patients, and help to stem the US opioid epidemic.
Public Health Relevance Statement: PROJECT NARRATIVE Never in the history of the United States has the unmet medical need to develop novel, non-opioid therapeutics for chronic pain been more urgent than it is today. Calpains are enzymes that have been shown to cause pain in many animal models of chronic pain. We propose to leverage our proprietary artificial intelligence (AI)-driven drug discovery platform to develop a selective calpain-1 inhibitor as a novel, non-opioid therapeutic for chronic pain.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Analgesics ; Analgesic Agents ; Analgesic Drugs ; Analgesic Preparation ; Anodynes ; Antinociceptive Agents ; Antinociceptive Drugs ; pain killer ; pain medication ; pain reliever ; painkiller ; Sickle Cell Anemia ; Hb SS disease ; HbSS disease ; Hemoglobin S Disease ; Hemoglobin sickle cell disease ; Hemoglobin sickle cell disorder ; sickle cell disease ; sickle cell disorder ; sickle disease ; sicklemia ; inhibitor/antagonist ; inhibitor ; Artificial Intelligence ; AI system ; Computer Reasoning ; Machine Intelligence ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; bone ; Brain ; Brain Nervous System ; Encephalon ; Calpain ; Ca2+-Activated Protease ; Calcium-Activated Neutral Protease ; Calcium-Activated Neutral Proteinase ; Calcium-Activated Protease ; Calcium-Dependent Neutral Protease ; Calcium-Dependent Neutral Proteinase ; Desminase ; Papain-Like Cysteine Protease ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cathepsins ; Cells ; Cell Body ; Communities ; Caspase ; Caspase Gene ; Cell-Death Protease ; Cysteine Endopeptidases ; Cysteine Protease ; Cysteine Proteinases ; ICE-like protease ; cystein protease ; cystein proteinase ; cysteine endopeptidase ; Disease ; Disorder ; Enzymes ; Enzyme Gene ; Family ; Recording of previous events ; History ; Homeostasis ; Autoregulation ; Physiological Homeostasis ; Human ; Modern Man ; Hyperalgesia ; Hyperalgesic Sensations ; hyperalgia ; Inflammation ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Libraries ; Ligation ; Closure by Ligation ; Liver ; hepatic body system ; hepatic organ system ; Mus ; Mice ; Mice Mammals ; Murine ; Pain ; Painful ; Permeability ; Pharmacology ; Plasma Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Solubility ; Spinal Cord ; Medulla Spinalis ; Spinal nerve structure ; Spinal Nerves ; Sulfonamides ; Synapses ; Synaptic ; synapse ; Testing ; Texas ; United States ; Universities ; Work ; Zymosan ; benzothiazole ; calpain inhibitor ; CANP-I ; calcium-activated neutral protease inhibitor ; Cathepsin L ; CATL ; CTSL Protein ; Major Excreted Protein ; chloride-cotransporter potassium ; K-Cl cotransporter ; KCl cotransporter ; Health Care Costs ; Health Costs ; Healthcare Costs ; delta opioid receptor ; δ OR ; δ ORs ; δ opioid receptors ; δ-OR ; δ-ORs ; δOR ; δORs ; chronic pain ; Data Set ; Dataset ; nerve injury ; neural injury ; base ; improved ; Chronic ; Clinical ; Phase ; Biochemical ; Medical ; Chemicals ; Training ; Hepatocyte ; Hepatic Cells ; Hepatic Parenchymal Cell ; Liver Cells ; diabetic ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Opioid ; Opiates ; non-opioid analgesic ; non-narcotic analgesic ; non-opiate analgesic ; non-opioid ; non-opioid therapeutics ; nonnarcotic analgesics ; nonopiate analgesic ; nonopioid ; nonopioid analgesics ; analog ; Peripheral nerve injury ; peripheral nerve crush injuries ; Collaborations ; Genetic ; Attenuated ; Inflammatory ; scaffolding ; scaffold ; mechanical ; Mechanics ; Oral ; neuropathic ; Neuropathy ; Route ; Performance ; success ; chemical library ; small molecule libraries ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Catalytic Core ; Catalytic Region ; Catalytic Site ; Catalytic Subunit ; Catalytic Domain ; Speed ; novel ; Reporting ; Modeling ; response ; drug development ; drug discovery ; CNS Nervous System ; Central Nervous System ; Neuraxis ; Short interfering RNA ; siRNA ; Small Interfering RNA ; m-calpain ; mu-calpain ; Molecular Interaction ; Binding ; protein expression ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Apoptosis-Related Cysteine Protease Caspase 1 ; CASP-1 ; CASP1 ; Caspase-1 ; Caspase-1 Gene ; ICE Protease ; IL-1 beta Convertase ; IL-1 beta-Converting Enzyme ; IL-1BC ; IL-1b Converting Enzyme ; IL1B-Convertase ; IL1BC ; IL1BCE ; Interleukin 1-B Converting Enzyme ; Interleukin 1-Beta Convertase ; Interleukin-1 Beta Converting Enzyme ; Interleukin-1 Converting Enzyme ; CASP1 gene ; Address ; Dose ; virtual library ; Data ; in vitro Assay ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Knock-out ; Knockout ; Development ; developmental ; painful neuropathy ; neuropathic pain ; virtual ; chronic neuropathic pain ; Chronic inflammatory pain ; innovation ; innovate ; innovative ; peptidomimetics ; peptide mimetic ; peptide mimic ; synaptic inhibition ; synapse inhibition ; mouse model ; murine model ; stem ; motor impairment ; movement impairment ; movement limitation ; addiction ; addictive disorder ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; in vitro activity ; efficacy testing ; pain behavior ; screening ; spared nerve ; opioid use ; opiate consumption ; opiate drug use ; opiate intake ; opiate use ; opioid consumption ; opioid drug use ; opioid intake ; efficacy study ; opioid epidemic ; opiate crisis ; opioid crisis ; pain model ; pain sensitivity ; pain reduction ; reduce pain ; chronic pain patient ; patient with chronic pain ; lead optimization ; side effect ; pharmacokinetics and pharmacodynamics ; PK/PD ; blood-brain barrier permeabilization ; BBB permeabilization ; BBB permeable ; blood-brain barrier permeable ; bloodbrain barrier permeabilization ; bloodbrain barrier permeable ; chronic pain management ;
