title: Safe use of the CXCR4 inhibitor ALX40-4C in humans.
abstract: ALX40-4C is a small peptide inhibitor of the chemokine receptor CXCR4 that can inhibit X4 strains of HIV-1. Prior to the discovery of chemokine receptors as the HIV coreceptors, ALX40-4C was used in phase I/II clinical trials to evaluate its therapeutic potential against HIV-1, making ALX40-4C the first anticoreceptor inhibitor to be tested in humans against HIV-1. Patients in the highest dose groups achieved ALX40-4C levels above the effective concentration of the drug for nearly the entire 1-month treatment period. ALX40-4C was well tolerated by 39 of 40 asymptomatic HIV-infected patients, despite the critical role of CXCR4 in normal development and hematopoiesis. No significant or consistent reductions in viral load were observed, but only 12 of the enrolled patients harbored virus types that used CXCR4. We also found that ALX40-4C interacts with the second extracellular loop of CXCR4 and inhibits infection exclusively by blocking direct virus-CXCR4 interactions.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Doranz
authors.forename: L G
authors.initials: LG
authors.lastname: Filion
authors.forename: F
authors.initials: F
authors.lastname: Diaz-Mitoma
authors.forename: D S
authors.initials: DS
authors.lastname: Sitar
authors.forename: J
authors.initials: J
authors.lastname: Sahai
authors.forename: F
authors.initials: F
authors.lastname: Baribaud
authors.forename: M J
authors.initials: MJ
authors.lastname: Orsini
authors.forename: J L
authors.initials: JL
authors.lastname: Benovic
authors.forename: W
authors.initials: W
authors.lastname: Cameron
authors.forename: R W
authors.initials: RW
authors.lastname: Doms
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line; D003257:Consumer Product Safety; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D019380:Anti-HIV Agents; C094365:N-alpha-acetyl-nona-D-arginine amide acetate; D009842:Oligopeptides; D019718:Receptors, CXCR4