2-deoxy-D-glucose as a potential drug against fusogenic viruses including HIV

Abstract

Most enveloped viruses fuse with host cells and catalyze fusion among host cells by expression of specific patterns of N-glycosylation on their envelope proteins. In the 1970s, it was observed that 2-deoxy-D-glucose (2DOG) and 2-fluoro-2-deoxy-D-mannose (2F2DOM) inhibited N-glycosylation of asparagine (Asn) sites on the external domain of viral envelope proteins. This effect led to the virus particles being non-fusogenic with greatly reduced infectivity and reduced ability to pass from cell to cell by catalyzing cell--cell fusion. At that time, this observation was not particularly important because viral diseases were readily prevented by vaccines and there was no known link between fusogenic viruses and cancer. Today, we are faced with a chronic and lethal viral disease (AIDS) caused by a virus (HIV) that mutates so quickly that we have not been able to produce a vaccine. Moreover, it is spreading among millions of people unable to afford more than basic medications. In addition, cell--cell fusion has been identified as an important, if not essential, step in the progression of abnormal cell clones to clinically significant cancer and fusogenic viruses have been shown to cause progression of some tumors. Here, we reiterate the hypothesize (first made in 1986 by Blough et al. [Blough HA, Pauwels R, De Clercq E, Cogniaux J, Sprecher-Goldberger S, Thiry L. Glycosylation inhibitors block the expression of LAV/HTLV-III (HIV) glycoproteins. Biochem Biophys Res Commun 1986; 141:33-8]) that 2DOG, 2F2DOM and related compounds, which interfere with normal N-glycosylation of virus envelope proteins, are attractive candidates for anti-fusogenic drugs that can be used against chronic virus diseases and cancers. This analysis also supports the concept of blocking N-acetylglucosaminyl-transferases with chloroquine or other drugs (proposed by Savarino et al. [Savarino A, Lucia MB, Rastrelli E et al. Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors. J Acquir Immune Defic Syndr 2004; 35:223-32]) as an anti-viral approach. These drugs may have broader utility and lower cost than drugs designed specifically to target the gp41 protein of HIV, which have become popular as viral-entry inhibitors for treatment of HIV/AIDS.