The aims of this project are the determination of the crystal structures of three Candida yeast aspartic proteinases and a rational drug design program of novel inhibitors to these enzymes. The inhibitors are designed for therapeutic intervention and the treatment of Candida fungemia infections in immunosuppressed and immunocompromised AIDS patients. In immunocompromised cancer and, more commonly, in immunosuppressed AIDS patients, a secondary infection is frequently the cause of death. Three yeasts of the genus Candida, C. albicans, C. tropicalis and C. parapsilosis secrete highly active aspartic proteinases into the external growth medium of the host. A direct correlation exists between the virulence of these yeasts and the secretion of the aspartic proteinase. Inhibition of these proteinases offers will block the invasive proteolytic stage of candida fungemia. Designed inhibitors developed from this program will offer new regimes for treatment of invasive fungemia. This is particularly important due to the increasing incidence of patients with an impaired immune system, as is the case in immunocompromised AIDS patients. The applicant has crystallized the recombinant aspartic proteinase from C. tropicalis yeast in a form suitable for diffraction studies. Currently the X-ray structure of this new proteinase is under investigation. The project plans to expand these structural analyses to include other recombinant proteinases derived from C. albicans and C. parapsilosis. Extension of the structural studies will include co-crystal complexes of classic aspartic proteinase inhibitors with these enzymes. With the data derived from these studies, second generation drug design will be pursued using modern approaches of molecular modelling and energy calculations, and finally performing the structural analyses of these second generation inhibitors as proteinase inhibitor complexes.
| Fusek, M; Smith, E; Foundling, S I (1995) Extracellular aspartic proteinases from Candida yeasts. Adv Exp Med Biol 362:489-500 |
