Application of one‐bead one‐structure approach to identification of nonpeptidic ligands

Staňková, Magda; Issakova, Olga; Sepetov, Nikolai F.; Krchňák, Viktor; Lam, Kit S.; Lebl, Michal

doi:10.1002/ddr.430330211

“…X is a mixture of all 45 amino acids and thus the length of the library varies between five and seven residues. We have characterized the library by the use of the model receptor streptavidin since this target has extensively been used in the screening of peptide libraries [15,[24][25][26][27][28][29][30][31][32][33]. Thus novel ligands can be compared to already known binders.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Screening of an Indexed Motif-Library Containing Non-proteinogenic Amino Acids

Østergaard¹,

Holm²

1997

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In an effort to increase the probability of finding novel peptides in resin-bound combinatorial libraries displaying affinity to various macromolecular targets, we increased the diversity of a solid-phase library considerably by synthesizing multiple structures on each bead - a motif-library - including 45 building blocks. The building blocks consist of L-aa, D-aa and eight hydrophobic non-proteinogenic alpha-amino acids. A library with the format O-Z0-1-O-Z0-1-O-XX-resin was synthesized giving the four motifs OOOXX, OZOOXX, OOZOXX, OZOZOXX corresponding to 364.500 different motifs (45(3) x 4 theoretical combinations). The positions O are defined amino acids while Z represents three mixtures pi, omega, phi, where pi is a mixture of polar and charged residues, omega is a mixture of aliphatic residues and phi is a mixture of aromatic residues. X represents a mixture of all 45 residues. The library was screened with the macromolecular target streptavidin which served as a model receptor. Binding peptides were sequenced by microsequencing. We included small amounts of norvaline and norleucine in the library, which served as index residues to be able to distinguish between LD-amino acids and other residues with the same retention time in the HPLC system. Beads that interact with the receptor were found, and the binding motifs that appeared had no homology to known binding motifs found in either L-aa or D-aa libraries, instead motifs with the non-proteinogenic residues L-phenylglycine, O-benzyl-L-hydroxyproline and O-benzyl-L-tyrosine dominated. The novel peptides inhibit binding of biotin to streptavidin but do not bind to avidin, and the affinity is higher than the peptides found in linear all L-aa peptide libraries.

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“…Combinatorial libraries resulting from splitpool synthesis are referred to as ''one-bead-onecompound'' libraries according to LEBL [24][25][26]. This is based on the fact that due to the nature of splitting and pooling the resin beads, each resin bead in a library contains multiple copies of (ideally) just one single compound.…”

Section: Methods and Techniques Ofmentioning

confidence: 99%

“…Combinatorial libraries may consist of compounds free in solution, or linked to a solid phase. FURKA and coworkers pioneered the split -pool synthesis method [19][20][21][22] for the synthesis of large peptide libraries in 1988; this approach is termed divide, couple, and recombine synthesis by other workers [24][25][26][27].…”

Section: Concept Of Combinatorial Chemistrymentioning

confidence: 99%

Combinatorial Chemistry

Tiebes

¹

,

Peters

²

2000

Ullmann's Encyclopedia of Industrial Chemistry

0

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The article contains sections titled: 1. Introduction 2. Concept of Combinatorial Chemistry 3. Methods and Techniques of Combinatorial Synthesis 3.1. Synthetic Strategies Towards Combinatorial Libraries 3.1.1. Split ‐ Pool Synthesis Towards Combinatorial Libraries 3.1.1.1. Techniques using Resin Beads 3.1.1.2. Tea‐Bag Method 3.1.2. Parallel Synthesis Towards Combinatorial Libraries 3.1.2.1. Reaction Apparatus using Resin Beads 3.1.2.2. Multipin Technique 3.1.2.3. Spatially Addressable Parallel Synthesis on Silica Wafer 3.1.3. Reagent Mixture Synthesis Towards Combinatorial Libraries 3.2. Synthetic Methodology for Organic Library Construction 3.2.1. Solid‐Phase Organic Synthesis 3.2.1.1. Solid Support, Linker, and Cleavage Strategies 3.2.1.2. Reaction Portfolio 3.2.2. Synthesis in Solution and Liquid‐Phase Synthesis 4. Characterization of Combinatorial Libraries 4.1. Analytical Characterization 4.2. Hit Identification in Combinatorial Libraries by High‐Throughput Screening 4.2.1. Strategies for Libraries of Compound Mixtures 4.2.1.1. On‐Bead Screening 4.2.1.2. Deconvolution 4.2.1.2.1. Iterative Deconvolution 4.2.1.2.2. Deconvolution by Positional Scanning 4.2.1.2.3. Deconvolution by Orthogonal Libraries 4.2.1.3. Encoding 4.2.1.4. Multiple Cleavable Linkers 4.2.2. Strategies for Libraries of Separate Single Compounds 4.2.3. Conclusion 5. Automation and Data Processing 5.1. Synthesis Automation and Data Processing 5.2. Automated Purification 6. Library Design and Diversity Assessment 6.1. Diversity Assessment for Selection of Building Blocks or Compound 6.2. Iterative Optimization Methods 7. Economic Aspects and Industrial Case Studies 8. Further Developments 8.1. Combinatorial Chemistry and Catalysis 8.2. Combinatorial Chemistry and Material Science

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“…The same authors have used alkylation and acylation reactions for creation of model libraries 323 as well as for libraries screened for pharmaceutically relevant targets (Scheme 11). Unnatural amino acids, aldehydes and carboxylic acids were used for construction of the library by use of reductive alkylation of the primary amino group by various aldehydes and acylation of the resulting secondary amino groups with diverse carboxylic acids 326,327 . A library was screened against streptavidin and the structure of active compounds was determined by mass spectroscopy 326 .…”

Section: Syntheses Of Non-peptidic Libraries and Tools For Their Prepmentioning

confidence: 99%

Molecular Diversity and Libraries of Structures: Synthesis and Screening

Rinnová

¹

,

Lebl²

1996

Collect. Czech. Chem. Commun.

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Library, or molecular diversity, approaches are a progressive tool in contemporary investigation of biological interactions and drug discovery. All library approaches include certain degree of rationality and cannot be therefore classified as random or irrational techniques. Reviewed techniques are complementary to so called "rational design"; they can serve either as a tool to generate a lead, or, on the other hand, to optimize a "designed" lead by rapid evaluation of structure-activity relationships. Combinatorial approaches are based on either a random or multiple principle which enables production of large number of diverse molecular structures that can be simultaneously screened and evaluated in a biological assay to find an optimal interacting molecule.

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Application of one‐bead one‐structure approach to identification of nonpeptidic ligands

Cited by 33 publications

References 32 publications

Synthesis and Screening of an Indexed Motif-Library Containing Non-proteinogenic Amino Acids

Synthesis and Screening of an Indexed Motif-Library Containing Non-proteinogenic Amino Acids

Combinatorial Chemistry

Molecular Diversity and Libraries of Structures: Synthesis and Screening

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