Non-Addictive Analgesic Discovery from Marine Microbial Natural Products

About This Grant

Project Summary: Chronic pain, widely considered the United States’ #1 public health crisis, is the most common cause of long-term disability in the world, affecting more than 25 million people in the US and nearly one third of the world’s population overall. Current pharmaceutical treatment options are broadly ineffective and often contribute severe side effects, including anxiety, heart disease, liver disease, and/or addiction. To address the enormous unmet public health challenge of peripherally-mediated chronic pain, novel phenotypic screening tools and new, non-addictive chemical entities that serve as pain therapeutics are urgently needed. Here, we propose a new collaboration that aims to discover novel, non-opioid and non-addictive analgesics from marine microbial resources and advance them to enter the Pain Therapeutics Development Program (PTDP). Our proposal exploits a recently developed phenotypic assay, developed through the HEAL Initiative, that leverages human induced pluripotent stem cell (hiPSC) sensory neurons and glia cultured on multi-well microelectrode arrays (MEAs). This allows long-term and high- content characterization of sensory neuron electrophysiology under baseline (spontaneous) and evoked (thermal and electrical stimulus) conditions. This moderate throughput, pain-physiology-relevant system for hit identification represents a unique approach to compound screening that has yet to be applied to natural product-derived analgesic discovery outside of the preliminary data provided in this proposal. We will employ this unique assay to screen an existing library of purified and structurally characterized marine microbial natural products and extract fraction libraries generated from a diverse and chemically rich culture collection of marine bacteria. We further exploit a new approach called Small Molecule In Situ Resin Capture (SMIRC) to access chemical space that is not available using culture dependent techniques. The hiPSC assay will be used to identify high-priority hits and guide the isolation of active compounds, which will be structurally characterized and tested for toxicity and addiction phenotypes to inform prioritization. A carefully planned workflow, including collaboration with a small biotech company focused on analgesic lead optimization, will maximize the discovery potential of this program.