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Antimicrobial Agents and Chemotherapy, October 2008, p. 3737-3744, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00265-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Activity of the Small Modified Amino Acid -Hydroxy Glycineamide on In Vitro and In Vivo Human Immunodeficiency Virus Type 1 Capsid Assembly and Infectivity

Samir Abdurahman,¹ Ákos Végvári,³ Masoud Youssefi,¹ Michael Levi,² Stefan Höglund,⁴ Elin Andersson,⁵ Peter Horal,⁵ Bo Svennerholm,⁵ Jan Balzarini,⁶ and Anders Vahlne^1*

Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden,¹ Tripep AB, Hälsovägen 7, SE-141 57 Huddinge, Sweden,² Clinical Protein Science, Department of Electrical Measurements, Lund University, SE-221 00 Lund, Sweden,³ Department of Biochemistry, Uppsala University, SE-751 23 Uppsala, Sweden,⁴ Department of Clinical Virology, University of Göteborg, SE-413 46 Göteborg, Sweden,⁵ Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium⁶

Received 26 February 2008/ Returned for modification 21 April 2008/ Accepted 10 July 2008

Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH₂), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH₂ itself but a metabolite thereof, -hydroxy-glycineamide (-HGA), that is responsible for the antiviral activity. We show that -HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. -HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, -HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

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* Corresponding author. Mailing address: Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Phone: 46 8 5858 1313. Fax: 46 8 5858 7931. E-mail: anders.vahlne{at}ki.se

Published ahead of print on 21 July 2008.

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Antimicrobial Agents and Chemotherapy, October 2008, p. 3737-3744, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00265-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.