HIV-1 IN strand transfer inhibitors: a focus on metal binding

Most active and selective strand transfer HIV-1 integrase (IN) inhibitors contain chelating functional groups that are crucial feature for the inhibition of the catalytic activities of the enzyme. In particular, diketo acids and their derivatives can coordinate one or two metal ions within the catalytic core of the enzyme. The present work is intended as a contribution to elucidate the mechanism of action of the HIV-IN inhibitors by studying the coordinative features of H2L1 (L-708,906), an important member of the diketo acids family of inhibitors, andH2L2, a model for S 1360, another potent IN inhibitor. Magnesium(II) and manganese(II) complexes of H2L1 and H2L2 were isolated and fully characterized in solution and in the solid state. The crystal structures of the manganese complex [Mn(HL2)2(CH3OH)2]*2CH3OH were solved by X-ray diffraction analysis. Moreover, the speciation models for H2L2 with magnesium(II) and manganese- (II) ions were performed and the formation constants of the complexes were measured. M(HL2)2 (M =Mg2+, Mn2+) was the most abundant species in solution at physiological pH. All the synthesized compounds were tested for their anti-IN activity, showing good results both for the ligand and the corresponding complexes. From analysis of the speciation models and of the biological data we can conclude that coordination of both metal cofactors could not be strictly necessary and that inhibitors can act as complexes and not only as free ligands.