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Antimicrobial Agents and Chemotherapy, January 2005, p. 40-44, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.40-44.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Glycine-Amide Is an Active Metabolite of the Antiretroviral Tripeptide Glycyl-Prolyl-Glycine-Amide

Department of Clinical Virology, University of Göteborg, Göteborg,¹ Division of Clinical Virology, Karolinska Institutet, Stockholm,² Department of Biochemistry, Biomedical Center, Uppsala University, Uppsala, Sweden,³ Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium⁴

Received 27 April 2004/ Returned for modification 20 July 2004/ Accepted 16 September 2004

The chemically modified tripeptide glycyl-prolyl-glycine-amide (GPG-NH₂) 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-NH₂), proline (P-OH), and glycine-amide (G-NH₂) from proteolytic cleavage may inhibit the replication of HIV-1 in vitro. PG-NH₂ has previously been shown to have a modest effect on HIV-1 replication. In the present study we show that G-NH₂ 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-NH₂ concentration that inhibited virus replication by 50% (IC₅₀) was equimolar to that of GPG-NH₂ and ranged from 3 to 41 µM. Transmission electron microscopy revealed that the effect of G-NH₂ on HIV-1 morphology was equivalent to that of GPG-NH₂ and showed disarranged capsid structures, indicating interference with capsid formation. Serial passage of HIV-infected cells with G-NH₂ for more than 20 subcultivations did not decrease the susceptibility to the compound. The results from this study suggest that GPG-NH₂ might act as a prodrug and that G-NH₂ is an active antiretroviral metabolite.

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