Inhibition of HIV-1 envelope-mediated fusion by synthetic batzelladine analogues.

Marine natural products that feature polycyclic guanidine motifs, such as crambescidins and batzelladines, are known to have antiviral activities toward some viruses including HSV and HIV. In this study we evaluated a synthetic library containing 28 batzelladine analogues, the structures of which encompass and surpass variations seen in natural batzelladines, for their ability to inhibit HIV-1 envelope-mediated cell-cell fusion. Clear structure-activity relationships were revealed and indicated that the best inhibitors of fusion were most similar in structure to natural batzelladine F, with IC50 values ranging from 0.8 to 3.0 microM. Proceeding from the earlier finding that some batzelladines block gp120-CD4 binding, modeling studies of inhibitors binding to the CD4 binding site on gp120 were carried out. The lowest energy models suggest a preferred orientation for inhibitor binding that is consistent with the observed structure-activity relationships.