title: Newly designed modifier prolongs the action of short-lived peptides and proteins by allowing their binding to serum albumin.
abstract: We found that human serum albumin (HSA) contains a single binding domain for derivatives of long-chain fatty acid (LCFA)-like molecules in which the carboxylate is replaced by sulfonate. Accordingly, we have synthesized 16-sulfo-hexadecanoic acid-N-hydroxysuccinimide ester [HO(3)S-(CH(2))(15)-CONHS], an agent that reacts selectively with the amino side chains of peptides and proteins. A macromolecule containing a single 16-sulfohexadecanoate moiety associating with albumin with a K(a) value of 0.83 ± 0.08 × 10(6) M(-1), a sufficient affinity to extend the actions in vivo of such short-lived peptides and proteins. Subcutaneous administration of insulin-NHCO-(CH(2))(15)-SO(3)(-) into mice facilitated a glucose-lowering effect 4.3 times in duration and 6.6 times in area under the curve (AUC) as compared to an in vitro equipotent amount of Zn(2+)-free insulin. Similarly, subcutaneous and intravenous administration of exendin-4-NHCO-(CH(2))(15)-SO(3)(-) to mice yielded prolonged and stable reduction in glucose level, 5-9-fold longer than that of exendin-4. Also, a single subcutaneous administration of human interferon-α2-[NH-CO-(CH(2))(15)-SO(3)(-)](3) to mice yielded circulating antiviral activity over a period of 40 h. In conclusion, a simple, hydrophilic reagent has been engineered, synthesized, and studied. Its linkage to peptides and proteins in a monomodified fashion yielded hydrophilic, prolonged acting derivatives, due to their acquired ability to associate with serum albumin after administration.
authors: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel. yoram.shechter@weizmann.ac.il
authors: Yoram
authors: Y
authors: Shechter
authors: Keren
authors: K
authors: Sasson
authors: Vered
authors: V
authors: Lev-Goldman
authors: Sara
authors: S
authors: Rubinraut
authors: Menachem
authors: M
authors: Rubinstein
authors: Mati
authors: M
authors: Fridkin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D015195:Drug Design; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D010455:Peptides; D012709:Serum Albumin