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bioRxiv · 10.64898/2026.04.22.720287

Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress

Fuchs, N.·Yuan, S.·Kuncewicz, K.·Elhamouly, M.·El gaamouch, F.·Gabr, M.
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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function and a promising therapeutic target in Alzheimers disease. While current strategies have largely focused on antibody-based agonists, alternative modalities capable of modulating TREM2 signaling remain underexplored. Here, we report the discovery of TREM2-binding cyclic peptides using a disulfide-constrained phage display library. Screening and biophysical validation identified multiple binders, with TREM2-6 and TREM2-12 exhibiting micromolar affinity. Both peptides modulated microglial responses in human iPSC-derived model of amyloid stress and in neuron-microglia co-cultures. Molecular dynamics simulations supported stable peptide-TREM2 interactions, with TREM2-12 displaying a more constrained binding mode. In vitro pharmacokinetic profiling revealed favorable plasma and intestinal stability but limited permeability, consistent with cyclic peptide scaffolds. Together, these findings establish cyclic peptides as a viable modality for targeting TREM2 and provide a foundation for the development of tunable neuroimmune therapeutics. Insert Table of Contents artwork here O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/720287v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@fbe978org.highwire.dtl.DTLVardef@9cd946org.highwire.dtl.DTLVardef@17cb644org.highwire.dtl.DTLVardef@a2669e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Fuchs, N., Yuan, S., Kuncewicz, K., Elhamouly, M., El gaamouch, F., Gabr, M.. 2026-04-25. Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses under Amyloid Stress. https://doi.org/10.64898/2026.04.22.720287

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