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bioRxiv · 10.64898/2026.10.15.759511

Discovery of a brain-penetrant CHI3L1 inhibitor as an oral modulator of neuroinflammation in Alzheimers disease

Upadhyay, S.·Zhang, L.·Kaur, B.·Calvo-Barreiro, L.·Teplova, M.·Gabr, M.
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Abstract

Chitinase-3-like protein 1 (CHI3L1) is elevated in Alzheimers disease (AD), but its role in glial dysfunction and therapeutic tractability remain unclear. Here, screening a 4.2-billion-compound DNA-encoded library identified DELC2, a brain-penetrant CHI3L1 modulator. Biophysical and crystallographic studies showed that DELC2 binds the CHI3L1 glycan-recognition groove within an aromatic-hydrophobic pocket centered on Trp99 and Trp352. DELC2 inhibited CHI3L1-RAGE association, suppressed CHI3L1-induced inflammatory signaling, reduced Gal-3-positive microglia, and restored amyloid-{beta} uptake in glial cultures. In human cerebrospinal fluid, CHI3L1 was elevated in AD and correlated with astrocytic NF-{kappa}B activation. DELC2 phenocopied CHI3L1 immunodepletion, whereas CHI3L1 add-back restored inflammatory and amyloid-{beta}-handling defects. Oral DELC2 achieved sustained unbound brain exposure in 5xFAD mice, improved cognitive performance, reduced multiple amyloid-{beta} species, and attenuated astrocytic and microglial inflammatory programs. These findings establish the CHI3L1 glycan-recognition groove as a druggable regulator of RAGE-associated glial dysfunction and identify DELC2 as a chemical scaffold for CHI3L1-directed therapy in AD.

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Upadhyay, S., Zhang, L., Kaur, B., Calvo-Barreiro, L., Teplova, M., Gabr, M.. 2026-10-21. Discovery of a brain-penetrant CHI3L1 inhibitor as an oral modulator of neuroinflammation in Alzheimers disease. https://doi.org/10.64898/2026.10.15.759511

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