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.

• Keywords
• Inhibitor, crystal structure, hydrogen bonds, noncovalent interactions, peptidomimetics,
• MeSH
• Aspartic Acid Endopeptidases antagonists & inhibitors   metabolism   MeSH
• Candida parapsilosis enzymology   MeSH
• Fungal Proteins antagonists & inhibitors   metabolism   MeSH
• Protease Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Peptidomimetics chemical synthesis   chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aspartic Acid Endopeptidases MeSH
• Fungal Proteins MeSH
• Protease Inhibitors MeSH
• Peptidomimetics MeSH
• SAPP1 protein, Candida parapsilosis MeSH Browser

Progressive cerebral deposition of amyloid beta occurs in Alzheimers disease and during the aging of certain mammals (human, monkey, dog, bear, cow, cat) but not others (rat, mouse). It is possibly due to different amino acid sequences at positions 5, 10 and 13. To address this issue, we performed series of 100 ns long trajectories (each trajectory was run twice with different initial velocity distribution) on amyloid beta (1-42) with the human and rat amino acid sequence in three different environments: water with only counter ions, water with NaCl at a concentration of 0.15 M as a model of intracellular Na(+) concentration at steady state, and water with NaCl at a concentration of 0.30 M as a model of intracellular Na(+) concentration under stimulated conditions. We analyzed secondary structure stability, internal hydrogen bonds, and residual fluctuation. It was observed that the change in ionic strength affects the stability of internal hydrogen bonds. Increasing the ionic strength increases atomic fluctuation in the hydrophobic core of the human amyloid, and decreases the atomic fluctuation in the case of rat amyloid. The secondary structure analyses show a stable α-helix part between residues 10 and 20. However, C-terminus of investigated amyloids is much more flexible showing no stable secondary structure elements. Increasing ionic strength of the solvent leads to decreasing stability of the secondary structural elements. The difference in conformational behavior of the three amino acids at position 5, 10 and 13 for human and rat amyloids significantly changes the conformational behavior of the whole peptide.

• MeSH
• Amyloid beta-Peptides chemistry   MeSH
• Sodium Chloride chemistry   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Rats MeSH
• Humans MeSH
• Molecular Sequence Data MeSH
• Osmolar Concentration MeSH
• Peptide Fragments chemistry   MeSH
• Surface Properties MeSH
• Protein Structure, Secondary MeSH
• Amino Acid Sequence MeSH
• Molecular Dynamics Simulation * MeSH
• Protein Stability MeSH
• Protein Structure, Tertiary MeSH
• Water chemistry   MeSH
• Hydrogen Bonding MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• amyloid beta-protein (1-42) MeSH Browser
• Amyloid beta-Peptides MeSH
• Sodium Chloride MeSH
• Peptide Fragments MeSH
• Water MeSH