# The use of DNA-encoded library (DEL) technology for the identification of therapeutic molecules to treat opioid use disorders (OUDs)

> **NIH NIH R43** · JILLION THERAPEUTICS INC. · 2024 · $399,884

## Abstract

PROJECT SUMMARY
The use of DNA-encoded library (DEL) technology for the identification of therapeutic molecules to
treat opioid use disorders (OUDs).
This Phase I SBIR project aims at the identification, using a novel DEL drug discovery platform, of small
molecular weight compounds that can bind to the receptor GPR26 belonging to the family of G-protein coupled
receptors (GPCRs) with the goal of restoring brain functions associated with the reward system without
affecting opioid receptors. Effects of opioids are mediated through GPCR μ-opioid receptors (MORs) and
indirectly through dopaminergic pathways via dopamine receptors. Some of these pathways, and the basal
ganglia signaling in general, were largely deciphered by us in the Greengard lab over the last three decades.
Morphine perturbs the mesolimbic dopaminergic system which is triggered in conditions of dependence and
withdrawal. Furthermore, morphine-dependency is associated with elevated cAMP levels, altering broad cAMP
signaling, in the striatum especially. GPCRs represent one of the most important therapeutic classes and many
of them remain largely understudied and without a known ligand (called orphan GPCRs or oGPCRs). We have
identified several oGPCRs strongly and selectively expressed in brain regions highly relevant for substance
use disorders (SUDs). Those represent a remarkable and unexploited opportunity to counteract OUDs in an
innovative way, and without targeting the opioid receptors directly. We are proposing to focus this program on
GPR26 that appears to be the strongest candidate, based on our knowledge and preliminary data, to modify
cAMP signaling and potentially rebalance the basal ganglia signaling. GPCRs drug discovery is hampered by
the need of large amounts of mostly non-physiological receptor protein (E. coli) for high-throughput screening
(HTS) and the need for a clear biological activity to perform HTS drug screening. Our research strategy is to
identify GPR26 binders addressing each of these limitations by using a DNA-encoded library (DEL) screening
approach that will allow small amounts of a physiological/high quality target to be used with very large
screening power (125 million entirely new and proprietary compounds) and a binding-based assay that is
activity-independent. The central hypothesis is that due to the very large number of compounds available to be
tested and the inherent diversity, it will be possible to identify efficiently, in a cost-effective way, compounds
that are high-affinity binders (pre-optimization) of GPR26. DEL screening protocols have been generated and
optimized focusing on minimizing the amount of protein to be used and on purifying protein targets from
mammalian cells. These steps will ensure that a physiological GPR26 version is used for screening purposes
and that screen duplicates will increase confidence and improve hits’ heuristic values determination. Aim 1 will
be dedicated to DEL screening campaigns and 125 millions of DEL c...

## Key facts

- **NIH application ID:** 11005426
- **Project number:** 1R43DA061688-01
- **Recipient organization:** JILLION THERAPEUTICS INC.
- **Principal Investigator:** Marc Flajolet
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,884
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005426

## Citation

> US National Institutes of Health, RePORTER application 11005426, The use of DNA-encoded library (DEL) technology for the identification of therapeutic molecules to treat opioid use disorders (OUDs) (1R43DA061688-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11005426. Licensed CC0.

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