N-TERMINAL TRUNCATION OF SALMON-CALCITONIN LEADS TO CALCITONIN ANTAGONISTS - STRUCTURE ACTIVITY RELATIONSHIP OF N-TERMINALLY TRUNCATED SALMON-CALCITONIN FRAGMENTS INVITRO AND INVIVO

Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, Nα-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, Nα-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6. Nα-acetyl-sCT-(8-32)-NH2, in several bioassays including plasminogen activator release from LLC-PK1 cells (pA2 = 7.31), cAMP production in UMR-106-06 cells (pA2 = 7.81), and in the fetal rat long bone resorption assay showed potent antagonistic properties. © 1992 Academic Press, Inc.