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.
|Number of pages||16|
|Publication status||Published - 2020 Sept|
Bibliographical noteFunding Information:
Author Contributions: S.K.: Performing most experiments, data curation, analysis, interpretation, and writing the original draft; S.L., H.L., S.J., S.P. and D.K.: HPLC and assistance in animal experiments; J.-W.Y., I.-S.Y., and D.S.M.: HPLC, data interpretation, and writing the review; Y.J. and Y.-S.J.: conceptualization, supervision, funding acquisition (Y.J.), data interpretation and writing—review and editing. All authors have read and agreed to the published version of the manuscript Funding: This research was funded by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A3B07045694). The APC was funded by the Brain Korea Plus program through the NRF funded by the Ministry of Education (22A20130012141).
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science