One‐bead–one‐structure combinatorial libraries

Lebl, Michal; Krchňák, Viktor; Sepetov, Nikolai F.; Seligmann, Bruce; Štrop, Petr; Felder, S; Lam, Kit S.

doi:10.1002/bip.360370303

Cited by 134 publications

(91 citation statements)

References 91 publications

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“…A problem is, however, that the chemistry used for the alternating synthesis of the tag and ligand must be compatible and thereby may restrict the use of chemistry associated with, for example, peptide synthesis. Additionally, there is a risk that the macromolecular target may bind to the coding part, although this can be avoided by synthesizing the encoding part only inside the bead and the ligand structure on the outside [42].…”

Section: Structure Determinationmentioning

confidence: 99%

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

Østergaard¹,

Holm²

1997

J. Peptide Sci.

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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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Section: Structure Determinationmentioning

confidence: 99%

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

Østergaard¹,

Holm²

1997

J. Peptide Sci.

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“…Key to the success of these pioneer studies was the capability to readily microsequence linear unblocked peptides or oligonucleotides. The focus of recent library efforts has shifted away from peptides and toward peptidomimetic and/or nonpeptide structures, which may be more stable and potentially provide a more diverse sampling of conformational space (6)(7)(8). This expansion in target range is accompanied by new challenges for reliable assembly strategies and efficient determination of covalent structures of active principles recognized and selected by the biological screening.…”

mentioning

confidence: 99%

“…[9][10][11]; (ii) spatially addressable syntheses in which the structure of a compound is deduced from its position on an array (2,(12)(13)(14); and (iii) split synthesis procedures, whereby compounds are built up on solid-phase beads, each of which has a unique history throughout the randomization steps and hence a unique structure-e.g., "one-bead-one-peptide" (4,6). The appropriate synthetic strategies can be modified in a number of ways so that with each component introduced by a combinatorial step, a conjugate "tag" is added in a parallel step; these coding sequences or tags are read subsequently to decode the steps used for the construction of the structure on any given bead.…”

mentioning

confidence: 99%

Enzyme-mediated spatial segregation on individual polymeric support beads: application to generation and screening of encoded combinatorial libraries.

Vagner

Bárány

Lam

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Proteolysis of short NO-protected peptide substrates bound to polyoxyethylene-polystyrene beads releases selectively free amino sites in the enzyme-accessible "surface" area, The substantial majority of functional sites in the "interior" of the polymeric support are not reached by the enzyme and remain uncleaved (protected). Subsequent synthesis with two classes of orthogonal protecting groupsNa_tert-butyloxycarbonyl (Boc) and Na_9-fluorenylmethyloxycarbonyl (Fmoc)-allows generation of two structures on the same bead. The surface structure is available for receptor interactions, whereas the corresponding interior structure is used for coding. Coding structures are usually readily sequenceable peptides. This "shaving" methodology was illustrated by the preparation of a peptide-encoded model peptide combinatorial library containing 1.0 x 105 members at -6-fold degeneracy. From this single library, good ligands were selected for three different receptors: anti-.8-endorphin antibody, streptavidin, and thrombin, and the binding structures were deduced correctly by sequencing the coding peptides present on the same beads.

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“…In addition to using modular synthetic chemistry, SHALs can also be created using bead-based combinatorial chemistry (41,42). A highly focused library can be synthesized on the beads, added to HLA-DR expressing cells, allowed to bind, and washed to remove unbound or weakly bound beads.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma

DeNardo¹,

Hok²,

Natarajan³

et al. 2007

Int J Oncol

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One‐bead–one‐structure combinatorial libraries

Cited by 134 publications

References 91 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

Enzyme-mediated spatial segregation on individual polymeric support beads: application to generation and screening of encoded combinatorial libraries.

Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma

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