Combinatorial Discovery of Peptide Dendrimer Enzyme Models Hydrolyzing Isobutyryl Fluorescein

Two 6750-membered one-bead-one-compound peptide dendrimer combinatorial libraries L (X4)8(LysX3)4(LysX2)2 LysX1 (X1−4 = 14 different amino acids or deletion, Lys = branching lysine residue) and AcL (with N-terminal acetylation) were prepared by split-and-mix solid phase peptide synthesis. Screening...

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Bibliographic Details
Published inACS combinatorial science Vol. 13; no. 3; pp. 310 - 320
Main Authors Maillard, Noélie, Biswas, Rasomoy, Darbre, Tamis, Reymond, Jean-Louis
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.05.2011
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Medicinal
Chemistry, Multidisciplinary
Combinatorial Chemistry Techniques
Dendrimers - chemistry
Esterases - chemistry
Fluorescein - chemistry
Fructose-Bisphosphate Aldolase - chemistry
Hydrolysis
Life Sciences & Biomedicine
Models, Chemical
Peptides - chemistry
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
combinatorial libraries
enzyme models
hydrolysis
isobutyryl fluorescein
peptide dendrimer
ALDOL
IDENTIFICATION
GENERAL-METHOD
LIBRARIES
BEAD
SILICA
LIGAND
BINDING
CATALYSTS
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Summary:Two 6750-membered one-bead-one-compound peptide dendrimer combinatorial libraries L (X4)8(LysX3)4(LysX2)2 LysX1 (X1−4 = 14 different amino acids or deletion, Lys = branching lysine residue) and AcL (with N-terminal acetylation) were prepared by split-and-mix solid phase peptide synthesis. Screening toward fluorogenic substrates for esterase and aldolase activities using the in silica off-bead assay (N. Maillard et al., J. Comb. Chem. 2009, 11, 667−675) and bead decoding by amino acid analysis revealed histidine containing sequences active against fluorescein diacetate. Isobutyryl fluorescein, a related hydrophobic fluorogenic substrate, was preferentially hydrolyzed by dendrimers from library AcL containing hydrophobic residues such as AcH3 (AcHis)8(LysLeu)4(LysVal)2 LysLysOH, compared to simple oligohistidine peptides as reference catalysts. Polycationic dendrimers from library L with multiple free N-termini such as H8 (His)8(LysβAla)4(LysThr)2 LysaProNH2 (aPro = (2S,4S)-4-aminoproline) showed stronger reactivity toward 8-acetoxypyrene-1,3,6-trisulfonate with partial acylation of N-termini. These experiments highlight the role of noncatalytic amino acids to determine substrate selectivity in peptide dendrimer esterase models.
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ISSN:2156-8952
2156-8944
DOI:10.1021/co200006z