Bait and switch strategy for obtaining catalytic antibodies with acyl-transfer capabilities

Janda, Kim D.; Weinhouse, Michael I.; Schloeder, Diane M.; Lerner, Richard A.; Benkovic, Stephen J.

doi:10.1021/ja00159a074

Cited by 101 publications

(37 citation statements)

References 2 publications

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“…Applying the bait-and switch approach [21,22] to templated polymers, the binding strength of the ternary template-metal ion-supporting ligand complex can be altered for subsequent recognition experiments by the choice of the metal ion, which, consequently, also changes the correlated binding properties of the metal coordinating matrix [23,24]. Following that procedure, a high-fidelity imprint can be obtained by using strong coordination between the target template and a metal complex during material preparation, while weak binding interactions are used to explore the prepared rebinding sites afterwards [23,24].…”

Section: Introductionmentioning

confidence: 99%

Designing selective sites in templated polymers utilizing coordinative bonds

Striegler

2004

Journal of Chromatography B

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Section: Introductionmentioning

confidence: 99%

Designing selective sites in templated polymers utilizing coordinative bonds

Striegler

2004

Journal of Chromatography B

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“…To date, the most common strategy for producing catalytic antibodies has involved immunization with carefully designed synthetic antigens such as transition state analogs to elicit antibodies that catalyze bond cleavage (see ref. 1 and references therein), electrostatically or sterically complementary antigens to induce specific catalytic residues in the binding pocket (2,3), and peptide-linked metal cofactors to generate cofactor-assisted catalytic antibodies (4). Alternatively, catalytic antibodies can be produced from existing noncatalytic antibodies by the covalent attachment ofcofactors (5) and by single-site mutagenesis (6).…”

Section: Introductionmentioning

confidence: 99%

Antibody remodeling: a general solution to the design of a metal-coordination site in an antibody binding pocket.

Roberts

Iverson

et al. 1990

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

101

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To develop a general approach to designing cofactor-binding sites for catalytic antibodies, we characterized structural patterns in the binding sites of antibodies and zinc enzymes. Superposition of eight sets of antibody light-and heavy-chain variable domains identified structurally conserved sites within the sequence-variable complementarity determining regions. The pattern for catalytic zinc sites included two ligands close in sequence, a sequence-distant ligand, and a main-chain hydrogen bond joining two ligands. In both the light-and heavy-chain variable domains, the stereochemistry of five structurally conserved sites general to all known antibody structures matched that of the zinc ligands of carbonic anhydrase: three residues on two hydrogen-bonded antiparallel f-strands. template-based multisite design proved successful for remodeling an antibody to contain a cofactor-binding site, without requiring further mutagenesis and screening. Combination of a specific light or heavy chain containing a catalytic metal site with a library of complementary chains raised to potential substrates or transition state analogs should greatly improve the production of catalytic antibodies with desired activities and specificities.Catalytic antibodies are powerful tools because the diversity of the immune response can be used to generate antibodies with specific binding properties. To date, the most common strategy for producing catalytic antibodies has involved immunization with carefully designed synthetic antigens such as transition state analogs to elicit antibodies that catalyze bond cleavage (see ref. 1 and references therein), electrostatically or sterically complementary antigens to induce specific catalytic residues in the binding pocket (2,3), and peptide-linked metal cofactors to generate cofactor-assisted catalytic antibodies (4). Alternatively, catalytic antibodies can be produced from existing noncatalytic antibodies by the covalent attachment ofcofactors (5) and by single-site mutagenesis (6).To reduce the currently required extensive screening and to increase the success rate for obtaining catalytic antibodies, we have chosen to develop a general approach for remodeling antibody complementarity determining regions (CDRs) to create predetermined cofactor-binding sites. Since the cloning and expression of the antibody repertoire in microorganisms allows separate light-and heavy-chain libraries to be combined in random pairs (7, 8), we can combine one chain designed to have a cofactor-binding site with a library of complementary chains raised against an appropriate substrate analog. These chimeric antibodies would mimic enzymes in having both a catalytic site, designed by sitedirected mutagenesis, and a binding site, created by the immune system. Here, we report the initial step towards this goal, the development and implementation of a general strategy for designing potentially catalytic metal cofactor sites in antibody light or heavy chains. By using our knowledge of the consensus three-dimensional s...

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“…32 Here, the N-oxide 3 was utilized as the hapten, following a Ôbait-and-switchÕ strategy 33,34 (Fig. 1).…”

mentioning

confidence: 99%

Squaric monoamide monoester as a new class of reactive immunization hapten for catalytic antibodies

Yamamoto

Ruiz

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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Bait and switch strategy for obtaining catalytic antibodies with acyl-transfer capabilities

Cited by 101 publications

References 2 publications

Designing selective sites in templated polymers utilizing coordinative bonds

Designing selective sites in templated polymers utilizing coordinative bonds

Antibody remodeling: a general solution to the design of a metal-coordination site in an antibody binding pocket.

Squaric monoamide monoester as a new class of reactive immunization hapten for catalytic antibodies

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