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).
