Minimization of Parathyroid Hormone Using Simultaneous Multiple Peptide Synthesis: Implications for Structure Based Drug Design
Parathyroid hormone (PTH), an 84 residue long polypeptide, acts on PTH-1 receptors in bone and kidney to control blood calcium levels. Synthetic PTH(l-34), one of the first peptide hormones to be chemically synthesized, has full biological activity  (EC50 for cAMP generation ≈2 nM). Based on previous peptide truncation studies that identified residues 15–31 as the principal receptor-binding domain and residues 1–14 as the principal signaling domain, PTH(1–14) was synthesized and found to have faint but measurable activity (EC50 ≈200 μM) . The peptide was prepared on a multiple peptide synthesizer and the crude peptide was found to be of high quality, as shown by HPLC and MALDI-MS, and could be used directly in bioactivity assays after a simple desalting step on a disposable C18 cartridge. This finding prompted us to use this approach to synthesize an extensive series of PTH(1–14) analogs with which we could define structure-activity relationships in the peptide and potentially improve potency. Within a short time (≈1.5 years) we generated and characterized over 200 PTH(1–14) analogs and have thus far improved potency at least 1,000 times.
KeywordsParathyroid Hormone Peptide Hormone Structure Base Drug Design Crude Peptide cAMP Generation