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

Abdurahman, Samir; Végvári, Ákos LU ; Levi, Micheal; Höglund, Stefan; Högberg, Marita; Tong, Weimin; Romero, Ivan; Balzarini, Jan and Vahlne, Anders (2009) In Retrovirology 6(34).
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 affects HIV-1 infectivity and capsid assembly. The 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-hydroxyglycineamide (α-HGA). Chemically... (More)
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 affects HIV-1 infectivity and capsid assembly. The 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-hydroxyglycineamide (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 GNH2-metabolite indeed was α-HGA.

Conclusions

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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Retrovirology
volume
6
issue
34
publisher
BioMed Central
external identifiers
  • wos:000265396300002
  • scopus:65449131619
ISSN
1742-4690
DOI
10.1186/1742-4690-6-34
language
English
LU publication?
yes
id
2bc27576-c6ba-48ef-bb7c-d29e89c8dacd (old id 1365880)
date added to LUP
2009-04-09 10:16:55
date last changed
2017-01-01 08:09:22
@article{2bc27576-c6ba-48ef-bb7c-d29e89c8dacd,
  abstract     = {Background <br/><br>
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. <br/><br>
Results <br/><br>
Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that affects HIV-1 infectivity and capsid assembly. The 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-hydroxyglycineamide (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 <br/><br>
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 GNH2-metabolite indeed was α-HGA. <br/><br>
Conclusions <br/><br>
 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.},
  author       = {Abdurahman, Samir and Végvári, Ákos and Levi, Micheal and Höglund, Stefan and Högberg, Marita and Tong, Weimin and Romero, Ivan and Balzarini, Jan and Vahlne, Anders},
  issn         = {1742-4690},
  language     = {eng},
  number       = {34},
  publisher    = {BioMed Central},
  series       = {Retrovirology},
  title        = {Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology},
  url          = {http://dx.doi.org/10.1186/1742-4690-6-34},
  volume       = {6},
  year         = {2009},
}