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.
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