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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<jats:sub>12<\/jats:sub>-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.<\/jats:p>","DOI":"10.1128\/aac.00827-09","type":"journal-article","created":{"date-parts":[[2009,10,6]],"date-time":"2009-10-06T01:21:07Z","timestamp":1254792067000},"page":"134-142","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":29,"title":["Long-Lasting Enfuvirtide Carrier Pentasaccharide Conjugates with Potent Anti-Human Immunodeficiency Virus Type 1 Activity"],"prefix":"10.1128","volume":"54","author":[{"given":"Thierry","family":"Huet","sequence":"first","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Kerbarh","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Schols","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, Leuven B-3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Clayette","sequence":"additional","affiliation":[{"name":"Neurovirology Department, SPI-Bio, CEA, 18 Route du Panorama, BP 6, Fontenay-aux-Roses 92265 Cedex, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ce\u0301cile","family":"Gauchet","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy","family":"Dubreucq","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Eurasante\u0301, 70 Rue du Docteur Yersin, Loos 59120, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loi\u0308c","family":"Vincent","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Eurasante\u0301, 70 Rue du Docteur Yersin, Loos 59120, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi","family":"Bompais","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Eurasante\u0301, 70 Rue du Docteur Yersin, Loos 59120, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romain","family":"Mazinghien","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Eurasante\u0301, 70 Rue du Docteur Yersin, Loos 59120, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Querolle","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnaud","family":"Salvador","sequence":"additional","affiliation":[{"name":"UMR 5180 CNRS, Universite\u0301 de Lyon, Universite\u0301 Lyon 1, Lyon F-69622, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Je\u0301ro\u0302me","family":"Lemoine","sequence":"additional","affiliation":[{"name":"UMR 5180 CNRS, Universite\u0301 de Lyon, Universite\u0301 Lyon 1, Lyon F-69622, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Lucidi","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Balzarini","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, Leuven B-3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurice","family":"Petitou","sequence":"additional","affiliation":[{"name":"Endotis Pharma, Parc Biocitech, 102 Avenue Gaston Roussel, Romainville 93230, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.59.2.284-291.1986"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-006-9059-5"},{"key":"e_1_3_2_4_2","unstructured":"Pegylated T20 polypeptide. 2006"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0190-9622(03)02099-1"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.10.3858-3870.2004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.19.10617-10627.2004"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6189183"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2006.03.001"},{"key":"e_1_3_2_10_2","first-page":"17","year":"1997","unstructured":"Bj\u00f6rk, I., and S. 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