Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled ReceptorRFA-DA-19-019 R43 Phase I SBIRPI: Sid A. labed The highly addictive properties of opioid drugs, coupled with routine over-prescription, have resulted in anational crisis. Accidental overdose by opioids has increased over 400% in the last 15 years, from ~8,000 opioid-related overdoses to more than 30,000 in 2015. The staggering cost of the opioid health crisis to the Americanpublic exceeds $50 billion annually, highlighting the need for safer therapeutics for pain management. Drs. KirillMartemyanov and Brock Grill at the Scripps Institute, Florida, have engineered a model system expressing afunctional mammalian opioid receptor (MOR) in the model nematode Caenorhabditis elegans for discovery ofopioid modulators. Using this system, they identified an orphan G Protein Coupled Receptor, GPR139, as anegative regulator of MOR signaling. In mammals, GPR139 is co-expressed with MOR in opioid-sensitive brainregions and influences MOR trafficking and signaling. Deletion of GPR139 in mice enhanced opioid-inducedinhibition of neuronal firing, increased the analgesic and rewarding effects of morphine, and reduced withdrawal. Previous efforts to target GPR139, which have largely focused on identification of small molecule agonists,has failed to produce a therapeutic candidate antagonist with favorable pharmacological properties. To addressthis unmet need, EvoDenovo will screen an innovative library of cyclic peptides (CPs) for new GPR139antagonists by combining two state-of-the-art C. elegans technologies exclusive to EvoDenovo: 1) InVivoDisplay: a high-throughput screening technology invented by EvoDenovo that can be used for peptide-baseddrug discovery that bypasses the necessity of peptide purification by directly feeding live recombinant E. coliclones, each expressing a different cyclic peptide, directly to nematodes expressing mammalian MOR andhuman GP139. This drastically reduces the cost and time for screening. 2) The anti-opioid behavior platformdeveloped at Scripps by Drs. Martemyanov and Gril that assesses the behavioral effects of opioids and identifiespharmacological outcomes of different drugs. The combination of both platforms, assisted by an automated C.elegans movement tracking system, will yield a powerful high throughput screening engine capable ofinterrogating thousands of recombinant peptides within a few days, all in a unique in vivo setup. GPR139antagonists identified using this assay would likely be missed by conventional screening protocols. EvoDenovouses CPs instead of linear peptides. The cyclization of peptides increases gut stability by eliminating vulnerableN- and C-termini, reduces susceptibility to proteolytic hydrolysis, and enhances membrane permeability. There are 2 specific aims: Aim 1: Perform a behavioral screen for cyclic peptide antagonists of GPR139 inC. elegans. Aim 2: Validate hits generated from the C. elegans platform in mammalian cell-based assays. ThisPhase I proposal will provide the foundation for a Phase II SBIR which will include a larger-scale screen andfollow-up on prioritizing CP hits, mammalian testing, and IND enabling studies.EvoDenovo RFA-DA-19-019/ PI: Sid A. Labed - Page 1 of 1
Public Health Relevance Statement: Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor
RFA-DA-19-019, R43 Phase I SBIR
PI: Sid A. Labed
Project Narrative
Accidental overdose by opioids has increased over 400% in the last 15 years, from ~8,000 opioid-related
overdoses to more than 30,000 in 2015, highlighting the need for safer therapeutics for pain management. Nearly
all FDA-approved medications prescribed for severe pain target the mu-opioid receptor (MOR). EvoDenovo is
developing a discovery pipeline to identify and validate first in class peptide-based antagonists of GPR139, a
novel receptor inhibitor of MOR, which, when blocked, mitigates the adverse effects of opiods, thereby reducing
their abuse liability.
EvoDenovo RFA-DA-19-019/ PI: Sid A. Labed Project Narrative - Page 1 of 1
Project Terms: | | | 