An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for
inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against
colitis,
4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with
acidic amino acids to yield 4-PBA-glutamic
acid (PBA-GA) and 4-PBA-aspartic
acid (PBA-AA) conjugates. The PBA derivatives were converted to
4-PBA in the cecal contents, and the conversion was greater with PBA-GA than that with PBA-AA. After
oral administration of PBA-GA (oral PBA-GA), up to 2.7 mM PBA was detected in the cecum, whereas
4-PBA was not detected in the blood, indicating that PBA-GA predominantly targeted the large intestine. In
2,4-dinitrobenzenesulfonic acid-induced
colitis in rats, oral PBA-GA alleviated the damage and
inflammation in the colon and substantially reduced the elevated levels of ER stress marker
proteins in the inflamed colon. Moreover, PBA-GA was found to be as effective as the currently used anti-IBD
drug,
sulfasalazine. In conclusion, PBA-GA is a colon-targeted
prodrug of
4-PBA and is effective against rat
colitis probably via the attenuation of ER stress in the inflamed colon.