title: Engineering prolonged-acting prodrugs employing an albumin-binding probe that undergoes slow hydrolysis at physiological conditions.
abstract: 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.
authors.affiliation: Department of Biological-Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Sasson
authors.forename: Y
authors.initials: Y
authors.lastname: Marcus
authors.forename: V
authors.initials: V
authors.lastname: Lev-Goldman
authors.forename: S
authors.initials: S
authors.lastname: Rubinraut
authors.forename: M
authors.initials: M
authors.lastname: Fridkin
authors.forename: Y
authors.initials: Y
authors.lastname: Shechter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000077270:Exenatide; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism*; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011355:Prodrugs; D012709:Serum Albumin; D014688:Venoms; D000077270:Exenatide; D005947:Glucose