Amphiphilic Anionic Analogues of Galactosylceramide:  Synthesis, Anti-HIV-1 Activity, and gp120 Binding

Abstract

We describe the synthesis together with the results of anti-HIV-1 activity and gp120-monolayer binding experiments of new galactosyl amphiphiles, analogues of galactosylceramide, an alternative receptor used by HIV to infect CD4 negative cells. These compounds consist of single- and double-chain amphiphiles containing one or two galactose residues. To favor their clustering into galactosyl-rich microdomains, their molecular structure contains also an amino group or several hydroxyls or anionic groups, such as carboxylate, sulfate, sulfonate, and phosphate. Among the 12 new galactosylated compounds reported, a specific anti-HIV activity, although moderate (IC(50) from 10 to 50 microM), was detected only for three of them, i.e., I-GalSer[CO2Na][C14], II-GalSer[C14][C7SO3Na], and II-GalSer[C2SO4Na][C14], which contain an anionic group. The marked increase of surface pressure which was observed upon addition of gp120 into the aqueous subphase underneath the monolayers containing these galactolipids indicated gp120 insertion into the monolayers, suggesting that binding of these three derivatives to HIV-1 gp120 may be responsible for their anti-HIV activity.

Synthesis of Aliphatic [carbonyl‐11C]Esters Using [11C]Carbon Monoxide

“…phenyl 4‐phenylbutanoate28 according to ref 32,. and methyl hydrogen dodecanoate33 according to the method described in ref 34…”

Glycosphingolipids in HIV/AIDS: The Potential Therapeutic Application

“…It has been suggested that GM3 is bound only by gp120 from R5 strains whereas Gb3 is bound by both X4 and R5 strains (Hammache et al, 1999). GSL analogues have been shown to inhibit HIV infection (Fantini et al, 1997, Faroux-Corlay et al, 2001, Garg et al, 2008, Lund et al, 2006, Weber et al, 2000and the efficacy of such analogues depends on the nature of both the carbohydrate and lipid moieties. In addition, GalCer binds to gp120 associated gp41 (Alfsen & Bomsel, 2002), the fusion heptad repeat C-terminal peptide of which, mediates viral/host membrane fusion (Shnaper et al, 2004).…”

“…Peptide analogues of the V3 loop of gp120, including those that define the GSL binding site, are effective as inhibitors of HIV-membrane fusion (Delezay et al, 1996, Savarino et al, 2003. Furthermore, analogues of galactosyl ceramide have been found to be protective against T cell infection in vitro, where the hydrophobic aglycone moiety of GalCer played an important role (Fantini, 2000, Fantini et al, 1997, Faroux-Corlay et al, 2001 …”

“…Despite the fact that the carbohydrate moiety of the GSL defines the specificity of binding interactions, the lipid-free sugar shows minimal binding activity , Mamelak et al, 2001a. Thus, gp120 binding to the GSL receptors is abrogated if the lipid moiety, that is the anchor to the cell membrane, is removed (Faroux-Corlay et al, 2001, Mylvaganam & Lingwood, 1999b, Villard et al, 2002.In the membrane bilayer, GSLs comprise three domainsthe external aqueous sugar domain, the internal liquid crystalline domain and the "interface" between them. The "interface" region modulates the receptor function of the carbohydrate in response to the liquid crystalline domain, and likely plays a role in lipid raft organization.…”

Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors

“…These compounds also have an amino group or several hydroxyls or anionic groups to allow for clustering into GalCer domains. Such compounds have more potent antiviral activity with an IC 50 in the 10-50 µM range [80]. Another approach has been to synthesize polymerizable analogs of beta-galactosyl ceramide.…”