HIV-PROTEASE AS A TARGET MOLECULE IN THE TREATMENT OF AIDS. J. P. Priestle, A. Fässler, G. Bold, H.-G. Capraro, J. Rösel, M. Tintelnot-Blomley, M. G. Grütter, Marc Lang, Pharmaceuticals Division, Ciba-Geigy, Ltd., CH-4002 Basel, Switzerland

The maturation of the Human Immunodeficiency Virus (HIV) is dependent on a protease that cleaves the gag- and the gag-pol polyprotein into individual, active proteins. The HIV-protease (HIV-Pr) is an aspartic protease composed of two identical subunits of 99 residues each. Each subunit donates one aspartyl residue to the active site, which possesses two-fold molecular symmetry. The HIV-protease cleaves substrates with preferentially large hydrophobic residues in P1/P1' (e.g. Phe, Tyr, Leu) and small either hydrophobic (e.g. Val, Ile) or hydrophilic (Asn) residues in P2/P2' . Substrate is bound in an extended conformation.

We found initial HIV-Pr inhibitors by screening compounds originally designed to inhibit renin, a human aspartic protease involved in blood pressure regulation. Thereby we identified CGP 43026, a peptide mimic with high affinity to both enzymes (IC₅₀ of 27nM and 17nM for HIV-Pr and renin, respectively). Optimization of this lead compound with respect to specificity vs. renin and pharmacokinetic properties was achieved based on structural investigations and modeling studies and afforded first CGP 53437 and ultimately CGP 61755, the actual development compound. Independently, a second class of compounds was evaluated which took advantage of the two-fold molecular symmetry of HIV-Pr. These pseudosymmetric inhibitors are less peptidic and synthetically less demanding. The typical representative, CGP 53820, displays an azapeptide derived moiety instead of the central hydroxyethyl dipeptide isostere. Compounds of this class are currently in preclinical investigation. Thus, examination of the crystallographic structures of inhibitors in complex with both HIV-1 and HIV-2 protease have provided the basis for modeling studies which have led to the discovery of potent and pharmacologically attractive anti-HIV agents suitable for clinical evaluation.