Important recent advances in chemical synthesis, from this laboratory and others, have provided powerful new strategies for the homogeneous assembly of """"""""biologic"""""""" targets, such as proteins, glycoproteins, and carbohydrates. With the development of increasingly sophisticated methods for the synthesis of glycans and peptides, and for the merger of these individual domains, it is possible to bring to bear the power of chemical synthesis on the assembly of therapeutically relevant biologic agents. The capacity to synthesize peptides, glycopeptides, proteins, and glycoproteins in homogeneous form will provide important opportunities. In contrast to biologically controlled processes, which often yield complex product mixtures, synthesis can allow for high levels of control in terms of product purity and homogeneity. Moreover, through recourse to chemical means, it is possible to achieve rapid and controlled syntheses of collections of analogs bearing mutations and constraints along the peptide backbone or in the glycan domain. Synthetic analogs bearing targeted amino acid or glycan mutations may be evaluated to examine the relative impact of individual structural features on stability, activity, and secondary structure. This proposal seeks to apply recent methodological advances in this field to the convergent syntheses of biologic targets and synthetic analogs. These synthetic structures will be evaluated in preclinical settings through collaborative efforts. In Project 1, we expect that the synthesis of the glycoprotein hematopoietic agent, erythropoietin (EPO) in homogeneous form will be achieved. Fully synthetic single glycoform EPO will be evaluated in biological studies, and a range of homogeneous EPO analogs will be synthesized with the goals of obtaining optimal stability and reactivity, and of identifying the minimum structural features required for activity. Project 2 anticipates the synthesis and evaluation of the osteoporosis therapeutic agent, human Parathyroid Hormone and analogs thereof, with the objective of identifying a structure that displays enhanced pharmacostability while preserving or even enhancing biological activity. Project 3 encompasses the synthesis and evaluation of the heterodimeric glycoprotein, thyroid stimulating hormone (TSH). Analog structures will be prepared with a view toward discovering TSH analogs with enhanced iodine uptake ability and pharmacostability. Project 4 seeks to identify the minimal glycopeptide sequence necessary to simulate the anti-inflammatory properties of the IgG Fc glycopeptide. The goal of Project 5 involves development of a series of carbohydrate-based anticancer vaccines and their advancement to clinical evaluation. Finally, Project 6 is directed toward the continuing development of peptide and glycopeptide ligation methods. In summary, we envision a multifaceted research program that integrates chemistry and translational development with a view to advancing the fields of both chemical synthesis and medicine.
This proposal seeks to accomplish the synthesis of biologically active peptides and glycopeptides with improved properties for medicinal application. Target structures include erythropoietin (EPO), parathyroid hormone (PTH), thyroid stimulating hormone (TSH), immunoglobulin G glycopeptide, and an array of carbohydrate-based anticancer vaccine constructs.
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|Wu, Xiangyang; Stockdill, Jennifer L; Park, Peter K et al. (2012) Expanding the limits of isonitrile-mediated amidations: on the remarkable stereosubtleties of macrolactam formation from synthetic seco-cyclosporins. J Am Chem Soc 134:2378-84|
|Brailsford, John A; Danishefsky, Samuel J (2012) Probing the stability of nonglycosylated wild-type erythropoietin protein via reiterative alanine ligations. Proc Natl Acad Sci U S A 109:7196-201|
|Townsend, Steven D; Tan, Zhongping; Dong, Suwei et al. (2012) Advances in proline ligation. J Am Chem Soc 134:3912-6|
|Wilson, Rebecca M; Stockdill, Jennifer L; Wu, Xiangyang et al. (2012) A fascinating journey into history: exploration of the world of isonitriles en route to complex amides. Angew Chem Int Ed Engl 51:2834-48|
|Wu, Xiangyang; Park, Peter K; Danishefsky, Samuel J (2011) On the synthesis of conformationally modified peptides through isonitrile chemistry: implications for dealing with polypeptide aggregation. J Am Chem Soc 133:7700-3|
|Shang, Shiying; Tan, Zhongping; Danishefsky, Samuel J (2011) Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH). Proc Natl Acad Sci U S A 108:5986-9|
|Tan, Zhongping; Shang, Shiying; Danishefsky, Samuel J (2011) Rational development of a strategy for modifying the aggregatibility of proteins. Proc Natl Acad Sci U S A 108:4297-302|
|Shang, Shiying; Tan, Zhongping; Dong, Suwei et al. (2011) An advance in proline ligation. J Am Chem Soc 133:10784-6|
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