# Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor

> **NIH NIH R43** · EVODENOVO, INC. · 2022 · $255,061

## Abstract

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 Summary
 The highly addictive properties of opioid drugs, coupled with routine over-prescription, have resulted in a
national 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 American
public exceeds $50 billion annually, highlighting the need for safer therapeutics for pain management. Drs. Kirill
Martemyanov and Brock Grill at the Scripps Institute, Florida, have engineered a model system expressing a
functional mammalian opioid receptor (MOR) in the model nematode Caenorhabditis elegans for discovery of
opioid modulators. Using this system, they identified an orphan G Protein Coupled Receptor, GPR139, as a
negative regulator of MOR signaling. In mammals, GPR139 is co-expressed with MOR in opioid-sensitive brain
regions and influences MOR trafficking and signaling. Deletion of GPR139 in mice enhanced opioid-induced
inhibition 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 address
this unmet need, EvoDenovo will screen an innovative library of cyclic peptides (CPs) for new GPR139
antagonists by combining two state-of-the-art C. elegans technologies exclusive to EvoDenovo: 1) InVivo
Display: a high-throughput screening technology invented by EvoDenovo that can be used for peptide-based
drug discovery that bypasses the necessity of peptide purification by directly feeding live recombinant E. coli
clones, each expressing a different cyclic peptide, directly to nematodes expressing mammalian MOR and
human GP139. This drastically reduces the cost and time for screening. 2) The anti-opioid behavior platform
developed at Scripps by Drs. Martemyanov and Gril that assesses the behavioral effects of opioids and identifies
pharmacological 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 of
interrogating thousands of recombinant peptides within a few days, all in a unique in vivo setup. GPR139
antagonists identified using this assay would likely be missed by conventional screening protocols. EvoDenovo
uses CPs instead of linear peptides. The cyclization of peptides increases gut stability by eliminating vulnerable
N- 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 in
C. elegans. Aim 2: Validate hits genera...

## Key facts

- **NIH application ID:** 10256110
- **Project number:** 1R43DA053844-01
- **Recipient organization:** EVODENOVO, INC.
- **Principal Investigator:** Sid Ahmed Labed
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $255,061
- **Award type:** 1
- **Project period:** 2022-04-15 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10256110

## Citation

> US National Institutes of Health, RePORTER application 10256110, Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor (1R43DA053844-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10256110. Licensed CC0.

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