Catalytic antibodies form the thematic thread of this program of experimental work aimed at an understanding of the basic mechanisms employed in antibodies which catalyze specific well-characterized chemical reactions. In addition, the program aims to make a wide-ranging exploration of novel methodologies for generation and production of libraries of molecules with novel forms. In Project 8, Drs. Lerner and Janda will embark upon a program to generate fully artificial antibodies, altering both the framework and the CDR portions of Fv fragments in a combinatorial manner to generate novel reactivities. Another focus of Project 8 will be the generation of libraries of dimeric motifs utilizing bacteriophage display techniques. Two types of molecules will be displayed, artificial dimeric amidases and artificial dimeric DNA-binding constructs, enamine intermediate in their mechanisms. In Project 11 Dr. Barbas will focus on antibodies that use a catalytic amine and an metabolism as well as being of practical utility for the formation of carbon-carbon bonds in synthetic organic chemistry. Novel methods will be used to select for catalytic turnover. These studies have medical relevance in the design and activation of prodrugs for the treatment of cancer. Project 11 is closely linked to Projects 9 the aldolase catalytic antibodies in complex with various substrate molecules. These aldolase antibodies catalyze reactions using the same mechanism as natural aldolase enzymes, but can react with a much greater range of substrates. The source of this substrate promiscuity will be investigated through structural (Project 9, 10) and dynamic (Project 9) studies, using NMR (Project 9) and X-ray crystallography (Project 10). The insights gained from the structural studies into catalytic mechanism will be an important aid in the assessment of the success of the design efforts in programming reaction mechanisms. These stud9ies are aimed at the broader overall goal of utilizing the catalytic antibody technology in therapy as well as in pure science. We believe that a number of the pieces are now in place, and that we are closer to this goal. The studies described in this project represent important new areas which should find applications in the areas of chemotherapeutics and in asymmetric organic synthesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA027489-23
Application #
6512537
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gallahan, Daniel L
Project Start
1980-05-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
23
Fiscal Year
2002
Total Cost
$1,575,513
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Zhu, Xueyong; Tanaka, Fujie; Lerner, Richard A et al. (2009) Direct observation of an enamine intermediate in amine catalysis. J Am Chem Soc 131:18206-7
Kamikubo, Yuichi; Kroon, Gerard; Curriden, Scott A et al. (2006) The reduced, denatured somatomedin B domain of vitronectin refolds into a stable, biologically active molecule. Biochemistry 45:3297-306
Zhu, Xueyong; Wentworth Jr, Paul; Kyle, Robert A et al. (2006) Cofactor-containing antibodies: crystal structure of the original yellow antibody. Proc Natl Acad Sci U S A 103:3581-5
Steiner, Derek D; Mase, Nobuyuki; Barbas 3rd, Carlos F (2005) Direct asymmetric alpha-fluorination of aldehydes. Angew Chem Int Ed Engl 44:3706-10
Suri, Jeff T; Ramachary, Dhevalapally B; Barbas 3rd, Carlos F (2005) Mimicking dihydroxy acetone phosphate-utilizing aldolases through organocatalysis: a facile route to carbohydrates and aminosugars. Org Lett 7:1383-5
Chowdari, Naidu S; Barbas 3rd, Carlos F (2005) Total synthesis of LFA-1 antagonist BIRT-377 via organocatalytic asymmetric construction of a quaternary stereocenter. Org Lett 7:867-70
Ramachary, Dhevalapally B; Barbas 3rd, Carlos F (2005) Direct amino acid-catalyzed asymmetric desymmetrization of meso-compounds: tandem aminoxylation/O-N bond heterolysis reactions. Org Lett 7:1577-80
Suri, Jeff T; Steiner, Derek D; Barbas 3rd, Carlos F (2005) Organocatalytic enantioselective synthesis of metabotropic glutamate receptor ligands. Org Lett 7:3885-8
Tanaka, Fujie; Fuller, Roberta; Barbas 3rd, Carlos F (2005) Development of small designer aldolase enzymes: catalytic activity, folding, and substrate specificity. Biochemistry 44:7583-92
Mase, Nobuyuki; Thayumanavan, Rajeswari; Tanaka, Fujie et al. (2004) Direct asymmetric organocatalytic Michael reactions of alpha,alpha-disubstituted aldehydes with beta-nitrostyrenes for the synthesis of quaternary carbon-containing products. Org Lett 6:2527-30

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