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Antimicrobial Agents and Chemotherapy, November 2009, p. 4852-4859, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00811-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Katrien O. François,1 Christophe Pannecouque,1 Joeri Auwerx,1 Virginia Lozano,2 Maria-Jésus Pérez-Pérez,2 Dominique Schols,1 and Jan Balzarini1*

Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium,1 Instituto de Quimica Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain2

Received 17 June 2009/ Returned for modification 23 July 2009/ Accepted 19 August 2009

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.

* Corresponding author. Mailing address: Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-337341. Fax: 32-16-337340. E-mail: jan.balzarini{at}rega.kuleuven.be

{triangledown} Published ahead of print on 31 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4852-4859, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00811-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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