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Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity

Artikel i vetenskaplig tidskrift
Författare Samir Abdurahman
Akos Vegvari
Masoud Youssefi
Michael Levi
Stefan Hoglund
Elin Andersson
Peter Horal
Bo Svennerholm
Jan Balzarini
Anders Vahlne
Publicerad i Antimicrobial Agents and Chemotherapy
Volym 52
Nummer/häfte 10
Sidor 3737-3744
ISSN 0066-4804
Publiceringsår 2008
Publicerad vid Institutionen för biomedicin, avdelningen för infektionssjukdomar
Sidor 3737-3744
Språk en
Länkar dx.doi.org/10.1128/AAC.00265-08
Ämnesord Anti-HIV Agents, pharmacology, Capsid Proteins, physiology, Drug Resistance, Viral, genetics, Glycine, analogs & derivatives, pharmacology, HIV Core Protein p24, drug effects, genetics, HIV Infections, drug therapy, virology, HIV-1, drug effects, genetics, pathogenicity, physiology, Hela Cells, Humans, Microbial Sensitivity Tests, Microscopy, Electron, Transmission, Mutation, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Virulence, drug effects, Virus Assembly, drug effects, Virus Replication, drug effects
Ämneskategorier Farmaceutisk vetenskap, Mikrobiologi

Sammanfattning

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-NH(2)), 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-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-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. alpha-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, alpha-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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