title: Development of HIV fusion inhibitors.
abstract: In the past 25 years, the worldwide AIDS epidemic has grown such that roughly 38 million people were estimated to be living with the disease worldwide at the end of 2003. The introduction of antiretroviral-based therapies, beginning in 1987, has enabled many to live with HIV as a chronic, rather than terminal, disease. However, the emergence and spread of drug-resistant strains highlights the continued need for new therapies with novel modes of action. In 2003, the FDA and EMEA approved enfuvirtide (Fuzeon), a 36 amino acid peptide derived from the natural gp41 HR2 sequence, as the first HIV fusion inhibitor. T-1249, a 39 amino acid fusion inhibitor, is active against viruses that develop resistance to enfuvirtide. The development of FIs and the processes to manufacture enfuvirtide and T-1249 on an unprecedented scale for peptide therapeutics are presented. Synthetic routes based on a combination of solid phase peptide synthesis and solution phase fragment condensation as well as the analytical controls necessary to insure a robust process are discussed.
authors.affiliation: Process Research and Development, Trimeris, Inc., Durham, Morrisville, NC, USA. sschneider@trimeris.com
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Schneider
authors.forename: Brian L
authors.initials: BL
authors.lastname: Bray
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Mader
authors.forename: Paul E
authors.initials: PE
authors.lastname: Friedrich
authors.forename: Mark W
authors.initials: MW
authors.lastname: Anderson
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Taylor
authors.forename: Natalia
authors.initials: N
authors.lastname: Boshernitzan
authors.forename: Toivo E
authors.initials: TE
authors.lastname: Niemi
authors.forename: Brian C
authors.initials: BC
authors.lastname: Fulcher
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Whight
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Reagan J
authors.initials: RJ
authors.lastname: Greene
authors.forename: Larry E
authors.initials: LE
authors.lastname: Stoltenberg
authors.forename: Maynard
authors.initials: M
authors.lastname: Lichty
mesh_terms: D015195:Drug Design; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D015394:Molecular Structure; D010446:Peptide Fragments / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide