Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology.
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 alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-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 alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA.


CONCLUSIONS
alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.
Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Samir.abdurahman@ki.se
Samir
S
Abdurahman
Akos
A
Végvári
Michael
M
Levi
Stefan
S
Höglund
Marita
M
Högberg
Weimin
W
Tong
Ivan
I
Romero
Jan
J
Balzarini
Anders
A
Vahlne
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D002213:Capsid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D044967:Serum / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D014771:Virion / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D036022:Capsid Proteins; C018556:glycine amide; D005998:Glycine