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1.
Biochem Pharmacol ; 85(7): 881-7, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23262278

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.


Subject(s)
Antifungal Agents/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Candida albicans/enzymology , Fungal Proteins/antagonists & inhibitors , Models, Molecular , Pepstatins/chemistry , Antifungal Agents/chemical synthesis , Aspartic Acid Endopeptidases/chemistry , Drug Design , Fungal Proteins/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Pepstatins/chemical synthesis , Structure-Activity Relationship
2.
J Pept Sci ; 15(4): 272-7, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19189272

ABSTRACT

The synthetic route to pepstatin derivatives by a solid phase peptide synthesis using either O-protected or O-unprotected statine as a building block has been investigated. Statine was prepared according to a modified literature procedure, whereas protection of its 3-hydroxyl moiety using tert-butyldimethylsilylchloride (TBSCl) provided the novel O-TBS-protected statine building block. The O-tert-butyldimethylsilyl (TBS)-protected statine approach provides an improved synthetic strategy for the preparation of statine-containing peptides as demonstrated by the synthesis of the pepstatin analogue iva-Val-Leu-Sta-Ala-Sta.


Subject(s)
Pepstatins/chemical synthesis , Amino Acid Sequence , Amino Acids/chemical synthesis , Amino Acids/chemistry , Chromatography, High Pressure Liquid , Fluorenes/chemical synthesis , Fluorenes/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Molecular Structure , Pepstatins/chemistry
3.
Chembiochem ; 5(5): 685-90, 2004 May 03.
Article in English | MEDLINE | ID: mdl-15122641

ABSTRACT

The stereochemical course of the recently isolated fluorination enzyme from Streptomyces cattleya has been evaluated. The enzyme mediates a reaction between the fluoride ion and S- adenosyl-L-methionine (SAM) to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA). Preparation of (5'R)-[5-(2)H(1)]-ATP generated (5'R)-[5-(2)H(1)]-5'-FDA in a coupled enzyme assay involving SAM synthase and the fluorinase. The stereochemical analysis of the product relied on (2)H NMR analysis in a chiral liquid-crystalline medium. It is concluded that the enzyme catalyses the fluorination with an inversion of configuration consistent with an S(N)2 reaction mechanism.


Subject(s)
Fluorides/chemistry , Methionine Adenosyltransferase/chemistry , Nucleic Acid Conformation , S-Adenosylmethionine/chemistry , Streptomyces/enzymology , Catalysis , Molecular Structure , S-Adenosylmethionine/chemical synthesis , Stereoisomerism , Streptomyces/metabolism
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