Antibody catalysis of enantio- and diastereo-selective aldol reactions
AssigneeThe Scripps Research Institute
InventorsCarlos F. Barbas, Richard A. Lerner, Guofu Zhong
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Abstract
Nine efficient aldolase antibodies were generated using hapten 2. This hapten combines, in a single molecule, structural components employed for reactive immunization with structural components employed for forming a transition state analog of the aldol reaction. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro-aldol reactions and exhibit enantio- and diastereo-selectivities opposite that of antibody 38C2.
Claims45
A hapten represented by the following structure:
- 11
- where n is greater than or equal to 2 and less than or equal to 8.
A transition state immunoconjugate represented by the following structure:
- 12
- where n is greater than or equal to 2 and less than or equal to 8.
A process for producing a catalytic monoclonal antibody for catalyzing an aldol reaction, the process comprising the following steps:
- Step A:
- eliciting an immune response within an immune responsive subject by injecting a sterile solution of a hapten-carrier protein, said hapten-carrier protein including a sulfone β-diketone hapten;
- then
- Step B:
- isolating and cloning an antibody producing cell from the immune responsive subject of said Step A which expresses a catalytic antibody for catalyzing the aldol reaction;
- and then
- Step C:
- isolating the aldolase catalytic antibody expressed by the antibody producing cell isolated and cloned in said Step B.
Antibody molecules or molecules containing antibody combining site portions that catalyze an aldol addition reaction produced according to the following method:
- Step A:
- eliciting an aldolase immune response within an immune response subject by vaccination with a sterile solution containing the appropriate concentration of an aldol transition state immunoconjugate, said aldol transition state immunoconjugate including a sulfone β-diketone hapten;
- then
- Step B:
- isolating and cloning an antibody producing cell from the immune responsive subject of said Step A which expresses a catalytic aldolase antibody;
- and then
- Step C:
- isolating the catalytic aldolase antibody expressed by the antibody producing cell isolated and cloned in said Step B.
An antibody producing cell which secretes antibody molecules or molecules containing antibody combining site portions that catalyze an aldol addition reaction, the antibody producing cell being produced according to the following method:
- Step A:
- eliciting an aldolase immune response within an immune response subject by vaccination with a sterile solution containing the appropriate concentration of the aldol transition state immunoconjugate, said aldol transition state immunoconjugate including a sulfone β-diketone hapten;
- and then
- Step B:
- isolating and cloning the antibody producing cell from the immune responsive subject of said Step A which expresses a catalytic aldolase antibody.
An improved process for catalyzing an aldol reaction between aldehyde and a ketone reactants, wherein the improvement comprises contacting said aldehyde and ketone reactants with antibody molecules or molecules containing antibody combining site portions that catalyze an aldol addition reaction produced according to the following method:
- Step A:
- eliciting an aldolase immune response within an immune response subject by vaccination with a sterile solution containing the appropriate concentration of an aldol transition state immunoconjugate, said aldol transition state immunoconjugate including a sulfone β-diketone hapten;
- then
- Step B:
- isolating and cloning an antibody producing cell from the immune responsive subject of said Step A which expresses a catalytic aldolase antibody;
- and then
- Step C:
- isolating the catalytic aldolase antibody expressed by the antibody producing cell isolated and cloned in said Step B.
An improved process for catalyzing an aldol reaction between aldehyde and ketone reactants, wherein the improvement comprises contacting said aldehyde and ketone reactants with antibody molecules selected from a group consisting of 85A2, 85C7, 92F9, 93F3, 84G3, 84G11, 84H9, 85H6 and 90G8.
An improved kinetic resolution of β-hydroxyketones from a racemic mixture by means of a retro-aldol reaction, wherein the improvement comprises catalyzing said retro-aldol reaction with antibody molecules or molecules containing antibody combining site portions that catalyze an aldol addition reaction produced according to the following method:
- Step A:
- eliciting an aldolase immune response within an immune response subject by vaccination with a sterile solution containing the appropriate concentration of an aldol transition state immunoconjugate, said aldol transition state immunoconjugate including a sulfone β-diketone hapten;
- then
- Step B:
- isolating and cloning an antibody producing cell from the immune responsive subject of said Step A which expresses a catalytic aldolase antibody;
- and then
- Step C:
- isolating the catalytic aldolase antibody expressed by the antibody producing cell isolated and cloned in said Step B.
An improved kinetic resolution of β-hydroxyketones from a racemic mixture by means of a retro-aldol reaction, wherein the improvement comprises catalyzing said retro-aldol reaction with antibody molecules selected from a group consisting of 85A2, 85C7, 92F9, 93F3, 84G3, 84G11, 84H9, 85H6 and 90G8.
Dependencies are inferred from the claim text.