For some time, the research connected to this program has been addressed to providing advances in the logic and practice of organic syntheses, and the application of these advances to challenging natural product target structures which exhibit biological profiles of interest. The program has come to include oligosaccharides and, more recently, polypeptides and glycopolypeptides, including glycoproteins. We refer to this family of projects as "Biologics." This renewal seeks to build on some highly promising progress in the Biologics domain.
Aim I builds on major advances in the synthesis of erythropoietin to enable, for the first time, the precise dissection of the effects of glycosylation on stability, folding and general "bio-performance." Aim II is related to the total synthesis of the granulocyte stimulating factors, GMCSF and GCSF. Again, we will be able to explore the effects of glycosylation in this series.
Aim III deals with human parathyroid hormone related protein (hPTHrP), a polypeptide known for its inhibitory effect on apoptosis in tumor cells. The main goal in this aim is the evaluation of hPTHrP as an anti-cancer target by the identification of D-peptide inhibitors of hPTHrP through mirror image phage display.
Aim I V 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.
Aim V seeks to exploit some major new methodological advances in what we term solid phase peptide ligation (SPPL). We see this as potentially a huge advance in the chemical synthesis of proteins and, particularly, mutant proteins. The protein and glycoprotein targets which would become accessible upon realization of this program include erythropoietin, human parathyroid hormone, hPTHrP, TSH, Ras, and insulin.
The proposal brings to bear the resources of target directed organic synthesis to create complex biologic level entities with opportunities for translation to medicine. Target structures include: erythropoietin (EPO), granulocyte macrophage colony-stimulating factor (GM-CSF), parathyroid hormone related protein (PTHrP), and thyroid stimulating factor (TSH).
|Roberts, Andrew G; Johnston, Eric V; Shieh, Jae-Hung et al. (2015) Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides. J Am Chem Soc 137:13167-75|
|Pham, Hung V; Paton, Robert S; Ross, Audrey G et al. (2014) Intramolecular Diels-Alder reactions of cycloalkenones: stereoselectivity, Lewis acid acceleration, and halogen substituent effects. J Am Chem Soc 136:2397-403|
|Zhang, Qiang; Johnston, Eric V; Shieh, Jae-Hung et al. (2014) Synthesis of granulocyte-macrophage colony-stimulating factor as homogeneous glycoforms and early comparisons with yeast cell-derived material. Proc Natl Acad Sci U S A 111:2885-90|
|Townsend, Steven D; Ross, Audrey G; Liu, Kai et al. (2014) Stereospecific cis- and trans-ring fusions arising from common intermediates. Proc Natl Acad Sci U S A 111:7931-5|
|Wang, Ting; Danishefsky, Samuel J (2013) Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles. Proc Natl Acad Sci U S A 110:11708-13|
|Wang, Ping; Dong, Suwei; Shieh, Jae-Hung et al. (2013) Erythropoietin derived by chemical synthesis. Science 342:1357-60|
|Peng, Feng; Grote, Robin E; Wilson, Rebecca M et al. (2013) Pattern recognition analysis in complex molecule synthesis and the preparation of iso-Diels-Alder motifs. Proc Natl Acad Sci U S A 110:10904-9|