Targeting chitinase-3-like protein-1 in pancolitis by a drug-repurposing approach

Pancolitis is a severe form of ulcerative colitis. Inflammation affects the entire colon and increases carcinogenesis. Standard therapies often reveal toxicities. We performed transcriptomics of ileum and colon biopsies from pancolitis patients and healthy individuals. We identified 77 differentially expressed genes in the ileum and 89 in the colon. Nine genes were overexpressed in both regions (TCL1A, DUOXA2, CC18, S100A8, CHI3L1, PTGDS, MMP3, CXCL1, and GREM1). We focused on CHI3L1 (chitinase-3-like protein-1) and confirmed its protein expression by immunohistochemistry. Based on gene expression data from the GEO database, ROC analyses identified CHI3L1 as a potential drug target. Kindlin-1^-/- and Kindlin-2^-/- knockout mice, displaying severe colitis symptoms, expressed high CHI3L1 protein levels, further supporting its potential as a drug target. Through virtual drug screening and molecular docking of 1575 FDA-approved drugs using the supercomputer MOGON, we identified 13 candidate drugs with the lowest binding energies (LBEs; -13.8 (±0.4) to -11.8 (± 0.1) kcal/mol) and predicted inhibition constants (pK_i; 0.1 (± 0.04) to 2.2 (± 0.4) nM). We experimentally confirmed the binding of velpatasvir to recombinant CHI3L1 using microscale thermophoresis (dissociation constant K_D: 45.86 ± 8.99 µM). In HT-29/B6 cells, velpatasvir attenuated selected CHI3L1-induced inflammatory gene responses without evidence of overt cytotoxicity at the concentrations used. In conclusion, the novelty of this project lies in identifying CHI3L1 as a potential inflammation-associated drug target and in the supercomputer-based screening and validation of velpatasvir as a lead compound for modulating CHI3L1-associated inflammatory signaling in pancolitis.