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bioRxiv · 10.64898/2026.06.29.735442

Selection of potent biologic antagonists of the cannabinoid GPCR CB2R from a constrained peptide library

leddy, r.·pal, a.·plant, j.·mcbrien, c.·Li, Y.·phelan, h.·linse, s.·Steiner, C.·Collins, C.·o'connell, d. j.
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Abstract

Dysregulated gut homing of leukocytes drives chronic inflammation in Crohns disease (CD). We employed phage display selection campaigns with libraries of stabilized, constrained peptides against endogenous conformation states of the cannabinoid receptor CB2R on human T cells, to discover novel receptor antagonists with potential to inhibit gut homing. Cluster and frequency analysis of 50,000 enriched sequences resulted in expression and functional characterisation of 10 protein candidates using assays of glucose uptake, ERK phosphorylation (pERK) and {beta}-arrestin recruitment. Each candidate antagonised CB2R activity with recorded IC50 values of between 5-10 nM. Cannabinoid receptor nanodisc binding experiments and FSEC confirmed CB2R selectivity. SLKC_09 with an IC50 of 5.4 nM, was studied in a mouse model of chronic ileitis where it significantly inhibited gut homing of CD4+ & CD8+ naive, effector and memory cell types. Our findings highlight an alternative route to therapeutic inhibition of leukocyte trafficking in CD with a biologic inhibitor of CB2R.

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leddy, r., pal, a., plant, j., mcbrien, c., Li, Y., phelan, h., linse, s., Steiner, C., Collins, C., o'connell, d. j.. 2026-07-03. Selection of potent biologic antagonists of the cannabinoid GPCR CB2R from a constrained peptide library. https://doi.org/10.64898/2026.06.29.735442

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