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Article: Effect of structural modification on the gastrointestinal stability and hepatic metabolism of α-aminoxy peptides

TitleEffect of structural modification on the gastrointestinal stability and hepatic metabolism of α-aminoxy peptides
Authors
KeywordsΑ-Aminoxy Peptide
Cytochrome P450 Enzyme
Gastrointestinal Stability
Hepatic Metabolism
Structural Modification
Issue Date2012
PublisherSpringer-Verlag Wien. The Journal's web site is located at http://www.springer.at/amino_acids
Citation
Amino Acids, 2012, v. 43 n. 5, p. 2073-2085 How to Cite?
Abstractα-Aminoxy peptide AxyP1 has been reported to form synthetic chloride channel in living cells, thus it may have therapeutic potential for the treatment of diseases associated with chloride channel dysfunction. However, this study revealed significant gastrointestinal (GI) instability and extensive hepatic metabolism of AxyP1. To improve its GI and metabolic stability, structural modifications were conducted by replacing the isobutyl side chains of AxyP1 with methyl group (AxyP2), hydroxymethyl group (AxyP3), 4-aminobutyl group (AxyP4) and 3-carboxyl propyl group (AxyP5). Compared with AxyP1 (41 and 47 % degradation), GI stability of the modified peptides was significantly improved by 8-fold (AxyP2), 9-fold (AxyP3) and 12-fold (AxyP5) with no degradation for AxyP4 in simulated gastric fluid within 1 h, and by 12-fold (AxyP2) and 9-fold (AxyP3) with no degradation for AxyP4 and AxyP5 in simulated intestinal fluid within 3 h, respectively. The hepatic metabolic stability of the four modified peptides within 30 min in rat liver S9 preparation was also improved significantly with no metabolism of AxyP5 and threefold (AxyP2 and AxyP4) and eightfold (AxyP3) less metabolism compared with AxyP1 (39 % metabolism). Unlike hydrolysis as the major metabolism of peptides of natural α-amino acids, oxidation mediated by the cytochrome P450 enzymes, especially CYP3A subfamily, to form the corresponding mono-hydroxyl metabolites was the predominant hepatic metabolism of the five α-aminoxy peptides tested. The present findings demonstrate that structural modification can significantly improve the GI and metabolic stability of α-aminoxy peptides and thus increase their potential for therapeutic use in the treatment of chloride channel related diseases. © 2012 Springer-Verlag.
Persistent Identifierhttp://hdl.handle.net/10722/168622
ISSN
2015 Impact Factor: 3.196
2015 SCImago Journal Rankings: 1.362
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, Ben_US
dc.contributor.authorYin, Cen_US
dc.contributor.authorYang, Den_US
dc.contributor.authorLin, Gen_US
dc.date.accessioned2012-10-08T03:21:42Z-
dc.date.available2012-10-08T03:21:42Z-
dc.date.issued2012en_US
dc.identifier.citationAmino Acids, 2012, v. 43 n. 5, p. 2073-2085en_US
dc.identifier.issn0939-4451en_US
dc.identifier.urihttp://hdl.handle.net/10722/168622-
dc.description.abstractα-Aminoxy peptide AxyP1 has been reported to form synthetic chloride channel in living cells, thus it may have therapeutic potential for the treatment of diseases associated with chloride channel dysfunction. However, this study revealed significant gastrointestinal (GI) instability and extensive hepatic metabolism of AxyP1. To improve its GI and metabolic stability, structural modifications were conducted by replacing the isobutyl side chains of AxyP1 with methyl group (AxyP2), hydroxymethyl group (AxyP3), 4-aminobutyl group (AxyP4) and 3-carboxyl propyl group (AxyP5). Compared with AxyP1 (41 and 47 % degradation), GI stability of the modified peptides was significantly improved by 8-fold (AxyP2), 9-fold (AxyP3) and 12-fold (AxyP5) with no degradation for AxyP4 in simulated gastric fluid within 1 h, and by 12-fold (AxyP2) and 9-fold (AxyP3) with no degradation for AxyP4 and AxyP5 in simulated intestinal fluid within 3 h, respectively. The hepatic metabolic stability of the four modified peptides within 30 min in rat liver S9 preparation was also improved significantly with no metabolism of AxyP5 and threefold (AxyP2 and AxyP4) and eightfold (AxyP3) less metabolism compared with AxyP1 (39 % metabolism). Unlike hydrolysis as the major metabolism of peptides of natural α-amino acids, oxidation mediated by the cytochrome P450 enzymes, especially CYP3A subfamily, to form the corresponding mono-hydroxyl metabolites was the predominant hepatic metabolism of the five α-aminoxy peptides tested. The present findings demonstrate that structural modification can significantly improve the GI and metabolic stability of α-aminoxy peptides and thus increase their potential for therapeutic use in the treatment of chloride channel related diseases. © 2012 Springer-Verlag.en_US
dc.languageengen_US
dc.publisherSpringer-Verlag Wien. The Journal's web site is located at http://www.springer.at/amino_acidsen_US
dc.relation.ispartofAmino Acidsen_US
dc.subjectΑ-Aminoxy Peptideen_US
dc.subjectCytochrome P450 Enzymeen_US
dc.subjectGastrointestinal Stabilityen_US
dc.subjectHepatic Metabolismen_US
dc.subjectStructural Modificationen_US
dc.titleEffect of structural modification on the gastrointestinal stability and hepatic metabolism of α-aminoxy peptidesen_US
dc.typeArticleen_US
dc.identifier.emailYang, D:yangdan@hku.hken_US
dc.identifier.authorityYang, D=rp00825en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1007/s00726-012-1291-1en_US
dc.identifier.pmid22526242-
dc.identifier.scopuseid_2-s2.0-84868152929en_US
dc.identifier.spage2073en_US
dc.identifier.epage2085en_US
dc.identifier.isiWOS:000309863400024-
dc.publisher.placeAustriaen_US
dc.identifier.scopusauthoridMa, B=51864116400en_US
dc.identifier.scopusauthoridYin, C=42361805500en_US
dc.identifier.scopusauthoridYang, D=7404800756en_US
dc.identifier.scopusauthoridLin, G=26643369300en_US
dc.identifier.citeulike10639063-

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