title: Preclinical evaluation of the HIV-1 fusion inhibitor L'644 as a potential candidate microbicide.
abstract: Topical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study, we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249, and L'644, was performed using cellular and ex vivo genital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol-derivatized version of C34, relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids, and the compound was still active when tissue explants were treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multiactive antiretroviral (ARV) combination-based microbicide. These data support the further development of L'644 for microbicide application.
authors.affiliation: Centre for Infection, Division of Cellular and Molecular Medicine, St George's University of London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Harman
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
authors.forename: Naomi
authors.initials: N
authors.lastname: Armanasco
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nuttall
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002584:Cervix Uteri / Q000187:drug effects / Q000473:pathology / Q000821:virology; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000821:virology; D004353:Drug Evaluation, Preclinical; D005260:Female; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation; D010413:Penis / Q000187:drug effects / Q000473:pathology / Q000821:virology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D046509:Tissue Culture Techniques; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C407149:peptide C34