Parathyroid hormone: chemistry and structure-activity relations

Peptide synthesis and the application of a wide range of biological assays have permitted intensive and detailed study of structure-activity relations for parathyroid hormone. Within the structure of the hormone molecule reside largely distinct domains critical for receptor binding or activation of adenylate cyclase in addition to receptor binding. Subtle modifications of hormonal structure can cause striking changes in hormone potency or in the nature of the biological properties displayed by such analogs. For parathyroid hormone, structure-activity studies have identified several discrete regions of the molecule that are responsible for independent biological functions. It was determined that these separate functions are displayed in an almost linear fashion along the primary sequence of the hormone--a conceptual framework that has greatly facilitated synthesis of parathyroid hormone analogs. The amino-terminal region of the initially biosynthesized precursor form of parathyroid hormone, pre-proparathyroid hormone, - 31 through - 7, contains a leader or signal sequence. Despite differences in sequence of the parathyroid hormone signal region and other precursor-specific sequences, this region of the molecule possesses biological properties related to intracellular transport and metabolism that appear to be universal for precursor forms of many, if not all, peptide hormones and other secreted proteins. In contrast, the amino-terminal portion of the secreted form of the molecule, sequence region 1-34, has an amino acid sequence that is homologous to that of several peptide hormones, including ACTH, alpha-MSH, beta-MSH, and beta-lipotropin. Yet the biological "message" conveyed by this peptide sequence appears unique to parathyroid hormone. Directions have now been established for the design of hormone inhibitors and for analogs of enhanced biological activity and perhaps even analogs possessing an altered spectrum of biological properties. The rapid advances that are occurring in techniques for peptide synthesis, purification, and analysis; in the variety, sensitivity, and specificity of the increasing number of bioassays; and in the elucidation of peptide and protein conformation may provide further important new directions for analog design. Extension of these investigations of structure and function over the next several years should yield a more sophisticated understanding of the mode of hormone action. In such studies lies the promise of generating highly refined and perhaps clinically useful analogs of parathyroid hormone.