# Elucidation of P2X7 Receptor Signaling and Development of Novel Small Molecule and Aptamer Ligand Therapies

> **NIH NIH DP2** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $1,340,100

## Abstract

PROJECT SUMMARY:
P2X purinergic receptors are trimeric, non-selective cation channels activated by extracellular ATP to modulate
processes in the cardiovascular and immune systems. The P2X7 receptor, the most structurally and functionally
distinct P2X receptor subtype, is involved in signaling pathways for apoptosis and inflammation, and is predicted
to play a key role in the link between inflammatory disease and atherosclerosis.In a mouse model of coronary
artery disease, gene knock-out P2X7 receptor deficiency abolished atherosclerosis, suggesting that development
of P2X7-specific antagonists to inhibit P2X7-signaling could result in a novel therapy for the prevention of coronary
artery disease. However, despite being an actively pursued pharmacologic target, there are no FDA-approved
drugs targeting the P2X7 receptor. Utilizing P2X receptors as a target for therapy has been hampered by a lack
of information defining the receptor’s structure and molecular mechanisms of function. Recently, my group
published the first atomic-resolution structures of full-length P2X7 receptor using single particle cryogenic
electron microscopy, changing this outlook. My structures demonstrated why the P2X7 receptor subtype does
not undergo desensitization and revealed that the cytoplasmic domain of P2X7 receptor has a novel fold without
structural homology to any fold in the Protein Data Bank, containing a high-affinity (nanomolar) guanosine
nucleotide binding site. This surprising finding in the cytoplasmic domain may begin to explain how activation of
the ionotropic P2X7 receptor recruits metabotropic secondary messenger systems, with the location of the
guanosine nucleotide binding site revealing where the receptor interfaces with intracellular signaling partners.
Understanding these processes and molecular interactions wouldexpand pharmaceutical strategies beyond
antagonism of P2X7 receptor at the extracellular domain to include modulating signaling at the cytoplasmic
domain. The major aim of this grant is to use my structures of P2X7 receptor as a platform to investigate its
unique signal transduction pathways and, using structure-based drug design, to develop novel ligands to
modulate P2X7 receptor function for therapeutic purposes. A transformative aspect of this proposal is expanding
the search of ligands targeting P2X7 receptor beyond small-molecules to include nucleic acid aptamers, a
Identification of ligands (either small molecule or
aptamer) that successfully inhibit P2X7 receptor activation or modulate P2X7 receptor intracellular signaling will
provide invaluable research tools for studying P2X receptors with the potential to be developed into therapies for
vascular inflammation and to prevent atherosclerosis.
promising paradigm heretofore unexplored in P2X receptors.

## Key facts

- **NIH application ID:** 10472269
- **Project number:** 1DP2GM149551-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Steven Elias Mansoor
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,340,100
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472269

## Citation

> US National Institutes of Health, RePORTER application 10472269, Elucidation of P2X7 Receptor Signaling and Development of Novel Small Molecule and Aptamer Ligand Therapies (1DP2GM149551-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10472269. Licensed CC0.

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