RATIONAL DESIGN, SYNTHESIS, AND CRYSTALLOGRAPHIC ANALYSIS OF A HYDROXYETHYLENE-BASED HIV-1 PROTEASE INHIBITOR CONTAINING A HETEROCYCLIC P-1' P-2' AMIDE BOND ISOSTERE

The rational design and synthesis of a highly potent inhibitor of HIV- 1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-1O1/HIV-1 protease co mplex and contains a 4(5)-acylimidazole ring as an isosteric replaceme nt for the P-1'-P-2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimension al structure of SB 206343 bound in the active site of HIV-1 protease h as been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (=Sigma paral lel to F-o\ - \F-c\\/Sigma\F-o\), of 0.194. The inhibitor is held in t he enzyme by a set of hydrophobic and polar interactions, N-3 of the i midazole ring participates in a novel hydrogen-bonding interaction wit h the bound water molecule, demonstrating the effectiveness of the imi dazole ring as an isosteric replacement for the P-1'-P-2' amide bond i n hydroxyethylene-based HIV-1 protease inhibitors. Also present are hy drogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxy gen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.