Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1996-06-19
1999-01-19
Weber, Jon P.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
530324, 530334, 435199, 435206, 435213, 435212, C07K 752, C07K 750, C12N 922, C12N 936, C12N 946, C12N 948
Patent
active
058614770
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
A. Field of the Invention
The present invention relates to chemically synthesized catalysts which are capable of catalyzing chemical reactions heretofore only efficiently catalyzed using naturally-occurring molecules. In particular, the invention pertains to catalytic compositions of matter and to catalyst chemical structures, to methods of producing the kinds of catalysts described, and to chemical reactions in which the catalytic compositions can be applied.
B. Description of the Related Art
For almost a century, catalytic macromolecules have occupied center-stage in life sciences and medicine because they catalyze many of the important chemical processes carried out in living organisms. In fact, one of the principal achievements of the modern pharmaceutical industry is the production of large quantities of such molecules for use in health care. More recently, the application of these catalysts in non-biological chemical processes has received the increasing interest of industrial chemists.
Entire enzyme molecules have been synthesized as a result of major advances in the knowledge of protein structure and solid-phase peptide chemistry. Some of these whole molecules retained the catalytic nature of the naturally-occurring enzyme. However, the molecules upon which the synthetic molecules were modeled were relatively small and the yields of the correct structures were extremely low due to the inherent limitations of solid-phase peptide synthesis. These failures made it evident that synthesizing whole enzymes merely to achieve the catalytic capability of the naturally occurring molecule was not a viable approach for the construction of commercial quantities of catalysts. Neither is this approach at all useful for larger enzymes which may comprise several hundreds of amino acid residues in their chains. Clearly, it would be highly desirable if it were possible to obtain the desired chemical activity without synthesizing the entire enzyme structure.
A short peptide was previously designed by the Applicant using surface-simulation synthesis to mimic the substrate-binding site of trypsin. This peptide was shown to possess the expected binding activities of the native enzyme with substrates and inhibitors (Atassi, M. Z., "Surface-Simulation Synthesis of the Substrate-Binding Site of an Enzyme," synthetically produced peptide had the ability to bind to substrates and competitive inhibitors, it exhibited no significant catalytic activity.
Artificial linear peptide was synthesized consisting of 34 residues the selection of which was based upon secondary structure prediction rules. A dimer of this peptide showed limited nuclease activity (Gutte, B., et al., Nature 281: 650-655 (1979). More recently and representative of this type of approach to synthetic catalyst design, an attempt was made to synthesize a portion of an enzyme molecule which would have a desired chemical activity. K. W. Hahn et al., "Design and Synthesis of a Peptide Having Chymotrypsin-Like Esterase Activity," Science, Vol. 248, pp. 1544-1547 (1990), describe the construction of a catalytic molecule in which four helical peptides were assembled in a bundle which contained at its amino ends, serine, histidine and aspartic acid in a spatial arrangement similar to that present in chymotrypsin (.alpha.CT). This assembled-helical design molecule contained 73 residues representing a major portion of and derived from the whole enzyme and was capable of binding to ester substrates of .alpha.CT. The assembled-helical design molecule was limited to hydrolyzing an acetyltyrosine ethyl ester for about 100 turnovers and was limited to a rate of catalysis which was only about 0.02% that of the native .alpha.CT. Importantly, the sequences in the marginally catalytic synthetic structure derived from the whole enzyme were substantially the same as the equivalent sequences found in the native enzyme.
Quite different approaches to attaining the chemical advantages of enzymes without having to rely on the native molecule have involved a un
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