title: Glycine-amide is an active metabolite of the antiretroviral tripeptide glycyl-prolyl-glycine-amide.
abstract: The chemically modified tripeptide glycyl-prolyl-glycine-amide (GPG-NH(2)) inhibits replication of human immunodeficiency virus (HIV) type 1 (HIV-1) in vitro, probably by interfering with capsid formation. The aim of the present study was to determine whether the metabolites glycyl-proline (GP-OH), glycine (G-OH), prolyl-glycine-amide (PG-NH(2)), proline (P-OH), and glycine-amide (G-NH(2)) from proteolytic cleavage may inhibit the replication of HIV-1 in vitro. PG-NH(2) has previously been shown to have a modest effect on HIV-1 replication. In the present study we show that G-NH(2) exhibits a pronounced inhibitory effect on HIV-1. This effect was not due to a decrease in cell proliferation or viability and could not be shown for herpes simplex virus type 1. The G-NH(2) concentration that inhibited virus replication by 50% (IC(50)) was equimolar to that of GPG-NH(2) and ranged from 3 to 41 microM. Transmission electron microscopy revealed that the effect of G-NH(2) on HIV-1 morphology was equivalent to that of GPG-NH(2) and showed disarranged capsid structures, indicating interference with capsid formation. Serial passage of HIV-infected cells with G-NH(2) for more than 20 subcultivations did not decrease the susceptibility to the compound. The results from this study suggest that GPG-NH(2) might act as a prodrug and that G-NH(2) is an active antiretroviral metabolite.
authors.affiliation: Department of Clinical Virology, University of Göteborg, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden. elin.andersson@microbio.gu.se
authors.forename: Elin
authors.initials: E
authors.lastname: Andersson
authors.forename: Peter
authors.initials: P
authors.lastname: Horal
authors.forename: Alenka
authors.initials: A
authors.lastname: Jejcic
authors.forename: Stefan
authors.initials: S
authors.lastname: Höglund
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Anders
authors.initials: A
authors.lastname: Vahlne
authors.forename: Bo
authors.initials: B
authors.lastname: Svennerholm
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D012692:Serial Passage; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; C018556:glycine amide; C425285:glycylprolylglycine amide; D005998:Glycine