Document Detail


TAC-scaffolded tripeptides as artificial hydrolytic receptors: a combinatorial approach toward esterase mimics.
MedLine Citation:
PMID:  18811207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this report, we present the first library of tripodal synthetic receptor molecules containing three different, temporarily N-terminal protected peptide arms capable of performing hydrolytic reactions. To construct this library, the orthogonally protected triazacyclophane (TAC)-scaffold was used in the preparation of a split-mix library of 19 683 resin bound tripodal receptor molecules. For the construction of the peptide arms, three different sets of amino acids were used, each focused on one part of the catalytic triad as found in several families of hydrolytic enzymes. Therefore, in the sets of amino acids used to assemble these tripeptides, basic (containing His and Lys), nucleophilic (containing Ser and Cys), or acidic (containing Asp and Glu) amino acid residues were present. In addition, nonfunctional hydrophobic amino acid residues were introduced. Possible unfavorable electrostatic interactions of charged N-termini or their acetylation during screening were circumvented by trifluoroacetylation of the N-terminal amines. Screening was performed with a known esterase substrate, 7-acetoxycoumarin, which upon hydrolysis gave the fluorescent 7-hydroxycoumarin, leading to fluorescence of beads containing a hydrolytically active synthetic receptor. Although many synthetic receptors contain catalytic triad combinations, apparently, only a few showed hydrolytic activity. Sequence analysis of the active receptors showed that carboxylate-containing amino acids are frequently found in the acidic arm and that substrate cleavage is mediated by lysine (noncatalytic) or histidine (catalytic) residues. Kinetic analysis of resynthesized receptors showed that catalysis depended on the number of histidine residues and was not assisted by significant substrate binding.
Authors:
H Bauke Albada; Rob M J Liskamp
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Publication Detail:
Type:  Journal Article     Date:  2008-09-24
Journal Detail:
Title:  Journal of combinatorial chemistry     Volume:  10     ISSN:  1520-4774     ISO Abbreviation:  J Comb Chem     Publication Date:    2008 Nov-Dec
Date Detail:
Created Date:  2008-11-10     Completed Date:  2008-12-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100886263     Medline TA:  J Comb Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  814-24     Citation Subset:  IM    
Affiliation:
Medicinal Chemistry and Chemical Biology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Binding Sites
Combinatorial Chemistry Techniques
Esterases / chemical synthesis*,  chemistry
Hydrolysis
Molecular Mimicry*
Oligopeptides / chemistry*
Small Molecule Libraries
Chemical
Reg. No./Substance:
0/Oligopeptides; 0/Small Molecule Libraries; EC 3.1.-/Esterases

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