title: Half-life extension of the HIV-fusion inhibitor peptide TRI-1144 using a novel linker technology.
abstract: We have previously developed a linker technology for half-life extension of peptides, proteins and small molecule drugs (1). The linkers undergo β-elimination reactions with predictable cleavage rates to release the native drug. Here we utilize this technology for half-life extension of the 38 amino acid HIV-1 fusion inhibitor TRI-1144. Conjugation of TRI-1144 to 40 kDa PEG by an appropriate β-eliminative linker and i.v. administration of the conjugate increased the in vivo half-life of the released peptide from 4 to 34 h in the rat, and the pharmacokinetic parameters were in excellent accord with a one-compartment model. From these data we simulated the pharmacokinetics of the PEG-TRI-1144 conjugate in humans, predicting a t1/2,β of 70 h for the released peptide, and that a serum concentration of 25 nM could be maintained by weekly doses of 8 μmol of the conjugate. Using a non-circulating carrier (2) similar simulations indicated a t1/2,β of 150 h for the peptide released from the conjugate and that dosing of only 1.8 μmol/week could maintain serum concentrations of TRI-1144 above 25 nM. Hence, releasable β-eliminative linkers provide significant half-life extension to TRI-1144 and would be expected to do likewise for related peptides.
authors.affiliation: ProLynx LLC, 455 Mission Bay Blvd. South, Suite 145, San Francisco, CA 94158, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Schneider
authors.affiliation: ProLynx LLC, 455 Mission Bay Blvd. South, Suite 145, San Francisco, CA 94158, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Ashley
authors.affiliation: Janssen Pharmaceutical Research, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Dillen
authors.affiliation: Janssen Pharmaceutical Research, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Stoops
authors.affiliation: Janssen Pharmaceutical Research, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Austin
authors.affiliation: Janssen Pharmaceutical Research, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Malcolm
authors.affiliation: ProLynx LLC, 455 Mission Bay Blvd. South, Suite 145, San Francisco, CA 94158, USA. Electronic address: Daniel.V.Santi@prolynxllc.com.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Santi
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006207:Half-Life; D006868:Hydrolysis; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010455:Peptides; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D011355:Prodrugs; C544608:T2635 peptide; D011092:Polyethylene Glycols
keywords: Combination therapy; Drug delivery; Half-life extension; Pegylation; Peptide drugs; Prodrug