This research program represents a collaboration between Professors Hirschmann/Smith at the University of Pennsylvania and Professor Benkovic at The Pennsylvania State University. The principal aim of the program is to produce catalytic antibodies which will promote efficient condensation of peptide fragments. The use of such antibodies to effect peptide bond formation should manifest the advantages of enzymatic peptide synthesis (i.e., minimal need for protecting groups, regiospecificity, and stereospecificity) and avoid the limitations associated with enzyme instability, enzyme-induced hydrolysis, and enzyme-related solubility problems, which result from the fact that enzymatic peptide synthesis is often carried out in mixed organic/aqueous systems. In addition, one will not be restricted by the repertoire of relevant, available enzymes. To test the potential of the concept, studies will first be directed towards the coupling of two dipeptides, one a suitably derivatized tyrosine carboxyl component and the other a D-tryptophan amino component in order to prepare tetrapeptide 3. The term, """"""""suitably derivatized carboxyl component"""""""" refers to an ester such as a p-nitrobenzyl ester which is to be a recognition site for the catalytic antibody as will be described. Once this or some other comparable simple coupling has been effected, it is planned t extend the concept to a series of antibodies whic would promote formation of any given peptide bond. The method will then be applied to the synthesis of polypeptides of ever increasing molecular weight. The implications of such a synthetic protocol in terms of peptide synthesis are tremendous. Assuming that the concept of using catalytic antibodies in fragment condensation typified by Eq.1 is viable and that it can be applied to the coupling of longer fragments, a suitable leap of faith would be to attempt to use a catalytic antibody to couple an appropriately C- terminally derivatized S-peptide to the corresponding S-protein. The reconstruction of ribonuclease A from its subtilism degradation products would be a dramatic demonstration of the scope of this approach. This has previously been achieved enzymatically.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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University of Pennsylvania
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Savinov, Sergey N; Hirschmann, Ralph; Benkovic, Stephen J et al. (2003) Investigation of an antibody-ligase. Evidence for strain-induced catalysis. Bioorg Med Chem Lett 13:1321-4
Smithrud, D B; Benkovic, P A; Benkovic, S J et al. (2000) Cyclic peptide formation catalyzed by an antibody ligase. Proc Natl Acad Sci U S A 97:1953-8
Hirschmann, R; Smith 3rd, A B; Taylor, C M et al. (1994) Peptide synthesis catalyzed by an antibody containing a binding site for variable amino acids. Science 265:234-7