Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores

Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The bin ding of the cosalanes to CD4 is proposed to involve ionic interactions of t he negatively charged carboxylates of the ligands with positively charged a rginine and lysine amino acid side chains of the protein. To investigate th e effect of anion spacing on anti-HIV activity in the cosalane system, a se ries of cosalane tetracarboxylates was synthesized in which the two proxima l and two distal carboxylates are separated by 6-12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic a cid, glycine, aspartic acid, beta -alanine, leucine, and phenylalanine resi dues, maximum activity was displayed by the di(glutamic acid) analogue. A h ypothetical model has been devised for the binding of the cosalane di(gluta mic acid) conjugate to CD4. In general, the compounds in this series are mo re potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.