The phthalocyanine prototype derivative Alcian Blue is the first synthetic agent with selective anti-human immunodeficiency virus activity due to its gp120 glycan-binding potential.
Alcian Blue (AB), a phthalocyanine derivative, is able to prevent infection by a wide spectrum of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains in various cell types [T cells, (co)receptor-transfected cells, and peripheral blood mononuclear cells]. With the exception of herpes simplex virus, AB is inactive against a broad variety of other (DNA and RNA) viruses. Time-of-addition studies show that AB prevents HIV-1 infection at the virus entry stage, exactly at the same time as carbohydrate-binding agents do. AB also efficiently prevents fusion between persistently HIV-1-infected HUT-78 cells and uninfected (CD4(+)) lymphocytes, DC-SIGN-directed HIV-1 capture, and subsequent transmission to uninfected (CD4(+)) T lymphocytes. Prolonged passaging of HIV-1 at dose-escalating concentrations of AB resulted in the selection of mutant virus strains in which several N-glycans of the HIV-1 gp120 envelope were deleted and in which positively charged amino acid mutations in both gp120 and gp41 appeared. A mutant virus strain in which four N-glycans were deleted showed a 10-fold decrease in sensitivity to the inhibitory effect of AB. These data suggest that AB is likely endowed with carbohydrate-binding properties and can be considered an important lead compound in the development of novel synthetic nonpeptidic antiviral drugs targeting the glycans of the envelope of HIV.
François
Katrien O
KO
Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Pannecouque
Christophe
C
Auwerx
Joeri
J
Lozano
Virginia
V
Pérez-Pérez
Maria-Jésus
MJ
Schols
Dominique
D
Balzarini
Jan
J
D000423:Alcian Blue / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D015726:Giant Cells / Q000187:drug effects; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009154:Mutation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D000423:Alcian Blue