| Engineering prolonged-acting prodrugs employing an albumin-binding probe that undergoes slow hydrolysis at physiological conditions. | |
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MedLine Citation:
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PMID: 19883707 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Here we describe the design and application of OSu-FMS-MAL-S-(CH(2))(15)-COOH, an agent that associates with albumin while linked to a peptide or a protein with sufficient affinity (Ka=2 to 2.6 x 10(5)M(-1)) to protract the action of short- lived peptides and proteins in vivo. Under physiological conditions this probe undergoes spontaneous hydrolysis with the concomitant reactivation of inactive conjugates. Intravenously administered (125)I-labeled-Insulin-FMS-MAL-S-(CH(2))(15)-COOH to rats shows half-life of 17+/-2h, exceeding 5.2 times that obtained with intravenously administered (125)I-labeled Insulin. In mice this derivative facilitates glucose-lowering effect over a period of 24h, yielding AUC five times greater than that obtained by a similar dose of insulin-detemir. Similarly, subcutaneous administration of Exendin-4-FMS-MAL-S-(CH(2))(15)-COOH into mice facilitated prolonged and stable reduction in glucose level, yielding a t(1/2) value of 28+/-2h, exceeding the effect of exendin-4 4.7 folds. The inactive derivative gentamicin-FMS-MAL-S-(CH(2))(15)-COOH regained its full antibacterial potency upon incubation at physiological conditions yielding a t(1/2) value of 7.1+/-0.2h. In conclusion, the albumin-binding probe we introduced enables to prolong the action of any amino containing molecule in vivo, without the drawback of inactivation that often occurs upon such derivatization. |
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Authors:
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K Sasson; Y Marcus; V Lev-Goldman; S Rubinraut; M Fridkin; Y Shechter |
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Publication Detail:
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Type: Journal Article Date: 2009-10-30 |
Journal Detail:
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Title: Journal of controlled release : official journal of the Controlled Release Society Volume: 142 ISSN: 1873-4995 ISO Abbreviation: J Control Release Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-17 Completed Date: 2010-06-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8607908 Medline TA: J Control Release Country: Netherlands |
Other Details:
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Languages: eng Pagination: 214-20 Citation Subset: IM |
Copyright Information:
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Copyright 2009 Elsevier B.V. All rights reserved. |
Affiliation:
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Department of Biological-Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Glucose / metabolism Humans Hydrolysis Hypoglycemic Agents / administration & dosage*, chemistry, metabolism, therapeutic use Insulin / administration & dosage*, chemistry, metabolism, therapeutic use Mice Molecular Sequence Data Peptides / administration & dosage*, chemistry, metabolism, therapeutic use Prodrugs / administration & dosage*, chemistry, metabolism, therapeutic use Protein Binding Rats Serum Albumin / metabolism* Venoms / administration & dosage*, chemistry, metabolism, therapeutic use |
| Chemical | |
Reg. No./Substance:
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0/Hypoglycemic Agents; 0/Peptides; 0/Prodrugs; 0/Serum Albumin; 0/Venoms; 11061-68-0/Insulin; 141732-76-5/exenatide; 50-99-7/Glucose |
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