Coupling Method of Oligomers

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Introduction Current approaches to the synthesis of polypeptide and peptidomimetic polymers are generally based on the coupling of individual monomer units through solid or solution phase chemistry. However, these approaches exhibit two inherent limitations: they are not compatible with the synthesis of sequence-specific long chain polymers; and they typically require chemical protecting groups. As an alternative, peptide ligation utilizing proteases to catalyze amide bond formation is a technique that can potentially surmount these limitations. However, there is still a need to overcome a major challenge of this approach in that the products themselves can be substrates for proteolytic cleavage. Description of the Project This invention allows oligomer fragment condensation for generating short or long chain length polymers while retaining control of the sequence specificity of the monomer units. Dr. Kirshenbaum and Mr. Yoo show in this invention that protease catalysis can be used to generate sequence-specific biomimetic macromolecules through the ligation of “peptoid” oligomers Peptoids, or N-substituted oligoglycines, are a class of peptidomimetic compounds that are inherently resistant to proteolytic cleavage, thus circumventing the limitations related to product degradation. The ligation reactions proceed efficiently because the peptoid fragments are functionalized with an enzyme recognition element, and the enzymatic catalysis allows for highly chemoselective bond formation between block units, thus precluding the need for protecting groups during ligation. In addition, the invention shows that that large concatemers of the starting oligomers having masses greater than 20 KDa can be obtained as the result of numerous ligation events under mild reaction conditions. Applications This invention will enable synthesis of large protein and protein-mimetic polymers, including biomaterials such as collagen and elastin. Collagen has a wide range of medical applications including biocompatible coatings, drug delivery, and tissue engineering. In addition, this invention allows for the incorporation of discrete biological and chemical functionalities into the naturally occurring polymer sequence for tailored biochemical and mechanical properties. Examples of this application include covalent cross-linking to improve biomaterial elasticity, or sequences containing specific chemical functionalities to improve the hydrating properties of the polymer material. Furthermore, this invention allows the mixing of natural and unnatural polymers to form hybrid macromolecular products resulting in materials with “tunable” properties.