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 of trans -4-l-Hydroxyprolyl-l-serine.

التفاصيل البيبلوغرافية
العنوان:	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 of trans -4-l-Hydroxyprolyl-l-serine.
المؤلفون:	Jiang Q; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., Xu Q; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., Wang Y; Department of Pharmacy, Linyi People's Hospital, Shandong University, Linyi 276002, China., Li P; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., Zhang Y; Changzhou Pharmaceutical Factory Company Ltd., Changzhou 213018, China., Wang Y; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., Sun J; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., Zhang T; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China., He Z; Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
المصدر:	Journal of medicinal chemistry [J Med Chem] 2022 Mar 24; Vol. 65 (6), pp. 4565-4577. Date of Electronic Publication: 2021 Nov 29.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة:	Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH:	Inflammatory Bowel Diseases/drug therapy , Peptide Transporter 1/chemistry , Symporters*/metabolism, Colon ; Dipeptides/chemistry ; Dipeptides/pharmacology ; Humans ; Serine/pharmacology
مستخلص:	The naturally occurring linear dipeptide JBP923 ( trans -4-l-Hyp-l-Ser, HS-tLL) with anti-inflammatory effects showed potential for the treatment of inflammatory bowel disease (IBD). However, colon-specific delivery after oral administration is still a challenge because its absorption is mediated by oligopeptide transporter 1 (PEPT1) in the upper small intestine and because of its instability in the gastrointestinal tract. Therefore, we aimed to enhance 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, and cis -4-d-Hyp-d-Ser did not work as substrates of PEPT1 and were stable in the gastrointestinal tract, resulting in enhanced colonic accumulation through the paracellular pathway due to the loose tight junctions in IBD. Interestingly, cis -4-d-Hyp-d-Ser exerted the most potent therapeutic effect on IBD. Our findings revealed the impact of chirality on the colonic accumulation of the linear dipeptide, providing strategies for the colon-targeted delivery of the linear dipeptide for the treatment of IBD.
المشرفين على المادة:	0 (Dipeptides) 0 (Peptide Transporter 1) 0 (SLC15A1 protein, human) 0 (Symporters) 452VLY9402 (Serine)
تواريخ الأحداث:	Date Created: 20211129 Date Completed: 20220506 Latest Revision: 20220531
رمز التحديث:	20221213
DOI:	10.1021/acs.jmedchem.1c01276
PMID:	34842428
قاعدة البيانات:	MEDLINE

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تدمد:	1520-4804
DOI:	10.1021/acs.jmedchem.1c01276