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A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

1
College of Pharmacy, Pusan National University, Busan 46241, Korea
2
College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Korea
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2020, 12(9), 843; https://doi.org/10.3390/pharmaceutics12090843
Received: 17 July 2020 / Revised: 17 August 2020 / Accepted: 26 August 2020 / Published: 3 September 2020
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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. View Full-Text
Keywords: 4-phenylbutyric acid; colon-targeted drug delivery; colitis; prodrug; endoplasmic reticulum stress; chemical chaperone 4-phenylbutyric acid; colon-targeted drug delivery; colitis; prodrug; endoplasmic reticulum stress; chemical chaperone
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MDPI and ACS Style

Kim, S.; Lee, S.; Lee, H.; Ju, S.; Park, S.; Kwon, D.; Yoo, J.-W.; Yoon, I.-S.; Min, D.S.; Jung, Y.-S.; Jung, Y. A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats. Pharmaceutics 2020, 12, 843. https://doi.org/10.3390/pharmaceutics12090843

AMA Style

Kim S, Lee S, Lee H, Ju S, Park S, Kwon D, Yoo J-W, Yoon I-S, Min DS, Jung Y-S, Jung Y. A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats. Pharmaceutics. 2020; 12(9):843. https://doi.org/10.3390/pharmaceutics12090843

Chicago/Turabian Style

Kim, Soojin, Seunghyun Lee, Hanju Lee, Sanghyun Ju, Sohee Park, Doyoung Kwon, Jin-Wook Yoo, In-Soo Yoon, Do S. Min, Young-Suk Jung, and Yunjin Jung. 2020. "A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats" Pharmaceutics 12, no. 9: 843. https://doi.org/10.3390/pharmaceutics12090843

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