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.
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.
Abdurahman
Samir
S
Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Végvári
Akos
A
Youssefi
Masoud
M
Levi
Michael
M
Höglund
Stefan
S
Andersson
Elin
E
Horal
Peter
P
Svennerholm
Bo
B
Balzarini
Jan
J
Vahlne
Anders
A
D019380:Anti-HIV Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000502:physiology; D024882:Drug Resistance, Viral / Q000235:genetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016655:HIV Core Protein p24 / Q000187:drug effects / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014774:Virulence / Q000187:drug effects; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D016655:HIV Core Protein p24; C514799:p24 protein, Human Immunodeficiency Virus Type 1; C018556:glycine amide; D005998:Glycine