title: Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
abstract: Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
authors.affiliation: Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France. thierryhuet@endotis.com
authors.forename: Thierry
authors.initials: T
authors.lastname: Huet
authors.forename: Olivier
authors.initials: O
authors.lastname: Kerbarh
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: Cécile
authors.initials: C
authors.lastname: Gauchet
authors.forename: Guy
authors.initials: G
authors.lastname: Dubreucq
authors.forename: Loïc
authors.initials: L
authors.lastname: Vincent
authors.forename: Heidi
authors.initials: H
authors.lastname: Bompais
authors.forename: Romain
authors.initials: R
authors.lastname: Mazinghien
authors.forename: Olivier
authors.initials: O
authors.lastname: Querolle
authors.forename: Arnaud
authors.initials: A
authors.lastname: Salvador
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lemoine
authors.forename: Bruno
authors.initials: B
authors.lastname: Lucidi
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D000991:Antithrombins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D000077560:Enfuvirtide; D065427:Factor Xa Inhibitors; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000821:virology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D000991:Antithrombins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D065427:Factor Xa Inhibitors; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D011134:Polysaccharides; D000077560:Enfuvirtide; D011092:Polyethylene Glycols