title: Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans.
abstract: The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease. Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates. Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position. These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6. Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans.
authors.affiliation: Department of Organic Chemistry, Free University Berlin, Takustrasse 3, D-14195 Berlin, Germany.
authors.forename: Cosimo D
authors.initials: CD
authors.lastname: Cadicamo
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mortier
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Marie
authors.initials: M
authors.lastname: Hell
authors.forename: Ina E
authors.initials: IE
authors.lastname: Heinrich
authors.forename: Dana
authors.initials: D
authors.lastname: Michel
authors.forename: Lydia
authors.initials: L
authors.lastname: Semlin
authors.forename: Ursula
authors.initials: U
authors.lastname: Berger
authors.forename: Hans C
authors.initials: HC
authors.lastname: Korting
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
authors.forename: Beate
authors.initials: B
authors.lastname: Koksch
authors.forename: Claudia
authors.initials: C
authors.lastname: Borelli
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002176:Candida albicans / Q000201:enzymology*; D015195:Drug Design; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D010436:Pepstatins / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D007527:Isoenzymes; D010436:Pepstatins; D016282:Aspartic Acid Endopeptidases