Pathogenic Candida albicans yeasts frequently cause infections in hospitals. Antifungal drugs lose effectiveness due to other Candida species and resistance. New medications are thus required. Secreted aspartic protease of C. parapsilosis (Sapp1p) is a promising target. We have thus solved the crystal structures of Sapp1p complexed to four peptidomimetic inhibitors. Three potent inhibitors (Ki: 0.1, 0.4, 6.6 nM) resembled pepstatin A (Ki: 0.3 nM), a general aspartic protease inhibitor, in terms of their interactions with Sapp1p. However, the weaker inhibitor (Ki: 14.6 nM) formed fewer nonpolar contacts with Sapp1p, similarly to the smaller HIV protease inhibitor ritonavir (Ki: 1.9 µM), which, moreover, formed fewer H-bonds. The analyses have revealed the structural determinants of the subnanomolar inhibition of C. parapsilosis aspartic protease. Because of the high similarity between Saps from different Candida species, these results can further be used for the design of potent and specific Sap inhibitor-based antimycotic drugs.

• Klíčová slova
• Inhibitor, crystal structure, hydrogen bonds, noncovalent interactions, peptidomimetics,
• MeSH
• aspartátové endopeptidasy antagonisté a inhibitory   metabolismus   MeSH
• Candida parapsilosis enzymologie   MeSH
• fungální proteiny antagonisté a inhibitory   metabolismus   MeSH
• inhibitory proteas chemická syntéza   chemie   farmakologie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• peptidomimetika chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aspartátové endopeptidasy MeSH
• fungální proteiny MeSH
• inhibitory proteas MeSH
• peptidomimetika MeSH
• SAPP1 protein, Candida parapsilosis MeSH Prohlížeč