Research

Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology

Samir Abdurahman¹ , Ákos Végvári³ , Michael Levi² , Stefan Höglund⁴ , Marita Högberg⁵ , Weimin Tong⁵ , Ivan Romero⁵ , Jan Balzarini⁶ and Anders Vahlne¹

¹  Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden

²  Tripep AB, Hälsovägen 7, SE-141 57 Huddinge, Sweden

³  Department of Electrical Measurements, Lund University, SE-221 00 Lund, Sweden

⁴  Department of Biochemistry, Uppsala University, SE-751 23 Uppsala, Sweden

⁵  Chemilia AB, SE-141 83 Huddinge, Sweden

⁶  Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

author email corresponding author email

Retrovirology 2009, 6:34doi:10.1186/1742-4690-6-34

Published:	8 April 2009

Abstract

Background

Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH₂) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures.

Results

Here we demonstrate that it is not G-NH₂ itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH₂ to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH₂ metabolite was α-hydroxy-glycineamide (α-HGA). Chemically synthesized α-HGA inhibited HIV-1 replication to the same degree as G-NH₂, unlike a number of other synthesized analogues of G-NH₂ which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized α-HGA further confirmed that the antiviral G-NH₂-metabolite indeed was α-HGA.

Conclusion

α-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, α-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.