Modulation of Naturally Occurring Linear Dipeptide Chirality to Reduce the Affinity for Oligopeptide Transporter 1 and Increase Intestinal Stability for an Enhanced Colon-Targeting Effect in the Treatment of Inflammatory Bowel Disease: An Application oftrans-4-L-Hydroxyprolyl-L-serine

The naturally occurring linear dipeptide JBP923(trans-4-L-Hyp-L-Ser, HS-tLL) with anti-inflammatory effectsshowed potential for the treatment of inflammatory bowel disease(IBD). However, colon-specific delivery after oral administration isstill a challenge because its absorption is mediated by oligopeptidetransporter 1 (PEPT1) in the upper small intestine and because ofits instability in the gastrointestinal tract. Therefore, we aimed toenhance the colon-targeting efficiency by modulating HS-tLL chirality to synthesize eight enantiomers. Among these enantiomers,trans-4-D-Hyp-D-Ser,cis-4-L-Hyp-D-Ser,cis-4-D-Hyp-L-Ser, andcis-4-D-Hyp-D-Ser did not work as substrates of PEPT1 and werestable in the gastrointestinal tract, resulting in enhanced colonic accumulation through the paracellular pathway due to the loosetight junctions in IBD. Interestingly,cis-4-D-Hyp-D-Ser exerted the most potent therapeutic effect on IBD. Ourfindings revealed theimpact of chirality on the colonic accumulation of the linear dipeptide, providing strategies for the colon-targeted delivery of thelinear dipeptide for the treatment of IBD.

Automated summary

By modulating the chirality of the linear dipeptide HS-tLL, the colon-targeting efficiency can be enhanced, providing a potential treatment for inflammatory bowel disease (IBD).