New bicyclam-GalCer analogue conjugates: synthesis and in vitro anti-HIV activity.

The synthesis of bipharmacophore anti-HIV compounds which, in a single molecule, combine two ligands, that is, the bicyclam AMD3100 and a GalCer analogue, that might inhibit several steps of the complex virus/cell cascade interactions has been performed. The 'double-drug' Gal-AMD3100 conjugates elicited inhibitory effects on T (or X4)-tropic HIV-1 replication in all CXCR4 expressing cell lines with EC(50) values ranging from 0.25 to 6.0 microM which were however approximately 40- to 125-fold lower than that of AMD3100. Concerning the mechanism of inhibition of the Gal-AMD3100 conjugates, experiments performed with X4 or R5HIV-1 strains and GHOST cells genetically modified to express CD4 and CXCR4 or CCR5 indicated clearly that the conjugates interact with CXCR4 and not with CCR5.