Discovery of membrane channel modulators via DNA encoded library screening using native like membrane protein nanoparticles.

Authors

Francesco V Reddavide, Trine L Toft-Bertelsen, Ieva Drulyte, Aspen Rene Gutgsell, Dzung Nguyen, Sara Bonetti, Katerina Vafia, Anne-Sophie Tournillon, Stephan Heiden, Daniel Grosser, Katarina Iric, Veronica Diez, Nanna MacAulay, Stefan Geschwindner, Michael Thompson, Jens Frauenfeld, Robin Löving

Published in

Scientific reports. Jun 15, 2026. Epub Jun 15, 2026.

Abstract

Developing novel drugs against membrane proteins is a major challenge in drug discovery due to the difficulty of stabilizing these targets for high-throughput screenings. Pannexin 1 (PANX1) is a membrane channel protein involved in various physiological and pathological processes, making it a promising target for drug discovery. However, efforts to develop PANX1-targeting therapeutics have been hindered by the inherent challenges of stabilizing the protein channel and conducting effective pharmacological screening. Here, we report a proof-of-concept workflow that integrates the Salipro lipid nanoparticle platform with DNA-Encoded Library screenings in a detergent-free format. In this case study, the Salipro DirectMX method was used to generate functional PANX1 nanoparticles for drug discovery and characterisation. Using a high-stringency selection strategy and computational approaches, we identified a specific set of candidate compounds with selective PANX1 enrichment. Surface Plasmon Resonance analysis confirmed the identification of hit compounds. Cryo-Electron Microscopy of the Salipro-PANX1-Compound complex provided structural insights into a potential compound binding site. Electrophysiological recordings in PANX1-expressing Xenopus laevis oocytes demonstrated dose-dependent inhibition of PANX1-mediated ion conductance by the compounds. These findings establish a robust workflow for ligand discovery against challenging membrane protein targets and provide novel chemical starting points for the development of PANX1 modulators.

PMID:
42298013
Bibliographic data and abstract were imported from PubMed on 16 Jun 2026.

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