Linked Life Data

21401109

Source:http://linkedlifedata.com/resource/pubmed/id/21401109

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2011-4-20
pubmed:abstractText
Dimerization is viewed as the most effective means of increasing receptor binding affinity, and both dimerization and PEGylation effectively prolong the life spans of short-lived peptides and proteins in vivo by delaying excretion via the renal route. Here, we describe the high binding affinities of two long-acting exendin-4 (Ex4) conjugates, dimerized Ex4 (Di-Ex4) and PEGylated Di-Ex-4 (PEG-Di-Ex4). Di-Ex4 and PEG-Di-Ex4 were prepared using cysteine and amine residue specific coupling reactions using Ex4-Cys, bisMal-NH(2), and activated PEG. The Ex4 conjugates produced were of high purity (>98.5%), as determined by size-exclusion chromatography and MALDI-TOF mass spectrometry. The receptor binding affinity of Di-Ex4 on RIN-m5F cells was 3.5-fold higher than that of Ex4, and the in vivo antihyperglycemic efficacy of Di-Ex4 was also greater than that of native Ex4 in type 2 diabetic db/db mice. Furthermore, Di-Ex4 and PEG-Di-Ex4 were found to have greater blood circulating t(1/2) and AUC(inf) values than native Ex4 by 2.7- and 13.7-fold, and by 4.0- and 17.3-fold, respectively. Accordingly, hypoglycemic durations were greatly increased to 15.0 and 40.1 h, respectively, at a dose of 25 nmol/kg (native Ex4 7.3 h). The results of this study show that combined dimerization and PEGylation are effective when applied to Ex4, and suggest that PEG-Di-Ex4 has considerable potential as a type 2 anti-diabetic agent.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1520-4812
pubmed:author
pubmed:issnType
Electronic
pubmed:day
20
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
625-32
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Mono-PEGylated dimeric exendin-4 as high receptor binding and long-acting conjugates for type 2 anti-diabetes therapeutics.
pubmed:affiliation
College of Pharmacy, SungKyunKwan University , 300 Chonchon-dong, Jangan-ku, Suwon City 440-746, Korea.
pubmed:publicationType
Journal Article