A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats

Soojin Kim; Seunghyun Lee; Hanju Lee; Sanghyun Ju; Sohee Park; Doyoung Kwon; Jin Wook Yoo; In Soo Yoon; Do Sik Min; Young Suk Jung; Yunjin Jung

doi:10.3390/pharmaceutics12090843

A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats

Soojin Kim, Seunghyun Lee, Hanju Lee, Sanghyun Ju, Sohee Park, Doyoung Kwon, Jin Wook Yoo, In Soo Yoon, Do Sik Min, Young Suk Jung, Yunjin Jung

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

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.

Original language	English
Article number	843
Pages (from-to)	1-16
Number of pages	16
Journal	Pharmaceutics
Volume	12
Issue number	9
DOIs	https://doi.org/10.3390/pharmaceutics12090843
Publication status	Published - 2020 Sept

Bibliographical note

Funding 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).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

Pharmaceutical Science

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10.3390/pharmaceutics12090843

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@article{bb7ea1ac15fe42098e97af9fc17a8175,

title = "A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats",

abstract = "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.",

author = "Soojin Kim and Seunghyun Lee and Hanju Lee and Sanghyun Ju and Sohee Park and Doyoung Kwon and Yoo, {Jin Wook} and Yoon, {In Soo} and Min, {Do Sik} and Jung, {Young Suk} and Yunjin Jung",

note = "Funding 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). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = sep,

doi = "10.3390/pharmaceutics12090843",

language = "English",

volume = "12",

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T1 - A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats

AU - Kim, Soojin

AU - Lee, Seunghyun

AU - Lee, Hanju

AU - Ju, Sanghyun

AU - Park, Sohee

AU - Kwon, Doyoung

AU - Yoo, Jin Wook

AU - Yoon, In Soo

AU - Min, Do Sik

AU - Jung, Young Suk

AU - Jung, Yunjin

N1 - Funding 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). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

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DO - 10.3390/pharmaceutics12090843

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ER -

A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats

Abstract

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