title: Albumin-conjugated C34 peptide HIV-1 fusion inhibitor: equipotent to C34 and T-20 in vitro with sustained activity in SCID-hu Thy/Liv mice.
abstract: Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505, was designed to require less frequent dosing and less peptide than T-20 and was assessed for its antifusogenic activity both in vitro and in vivo in the SCID-hu Thy/Liv mouse model. PC-1505 was essentially equipotent to the original C34 peptide and to T-20 in vitro. In HIV-1-infected SCID-hu Thy/Liv mice, T-20 lost activity with infrequent dosing, whereas the antiviral potency of PC-1505 was sustained, and PC-1505 was active against T-20-resistant ("DIV") virus with a G36D substitution in gp41. The in vivo results are the direct result of a significantly improved pharmacokinetic profile for the C34 peptide following albumin conjugation. Contrary to previous reports that the gp41 NHR trimer is poorly accessible to C34 fused to protein cargoes of increasing size (Hamburger, A. E., Kim, S., Welch, B. D., and Kay, M. S. (2005) J. Biol. Chem. 280, 12567-12572), these results are the first demonstration of the capacity for a large, endogenous serum protein to gain unobstructed access to the transient gp41 intermediates that exist during the HIV fusion process, and it supports further development of albumin conjugation as a promising approach to inhibit HIV-1 entry.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California 94110, USA. cheryl.stoddart@ucsf.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
authors.forename: Geneviève
authors.initials: G
authors.lastname: Nault
authors.forename: Sofiya A
authors.initials: SA
authors.lastname: Galkina
authors.forename: Karen
authors.initials: K
authors.lastname: Thibaudeau
authors.forename: Peter
authors.initials: P
authors.lastname: Bakis
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bousquet-Gagnon
authors.forename: Martin
authors.initials: M
authors.lastname: Robitaille
authors.forename: Maryanne
authors.initials: M
authors.lastname: Bellomo
authors.forename: Véronique
authors.initials: V
authors.lastname: Paradis
authors.forename: Patricia
authors.initials: P
authors.lastname: Liscourt
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lobach
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Rivard
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Marie K
authors.initials: MK
authors.lastname: Mankowski
authors.forename: Dominique
authors.initials: D
authors.lastname: Bridon
authors.forename: Omar
authors.initials: O
authors.lastname: Quraishi
mesh_terms: D000418:Albumins / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014760:Viral Fusion Proteins / Q000737:chemistry*
chemical_list: D000418:Albumins; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; C534488:PC 1505; D010446:Peptide Fragments; D010455:Peptides; D014760:Viral Fusion Proteins; C407149:peptide C34; D000077560:Enfuvirtide