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Vol. 54, Issue 5, 864-873, November 1998
Molecular and Cellular Biology (W.R.B., T.A.C., B.B., C.M.E.,
J.R.Z.) and
Molecular Genetic Screen Design (M.H.P., L.A.P.), American
Cyanamid Company, Princeton, New Jersey 08543, Division of
Neurophysiology and Neuropharmacology (D.C., I.C.A.F.R.), National
Institute of Medical Research, Mill Hill, London, UK, and
Torrey Pines
Institute for Molecular Studies, San Diego, California 92121 (R.H.)
Somatostatin (SRIF) is the main inhibitory peptide regulating growth
hormone (GH) secretion. It has been difficult to establish the role of
endogenous SRIF release in the absence of pure SRIF antagonists.
Although several SRIF antagonists have recently been described, none
have been shown to possess in vivo activity in the
absence of added SRIF. Here, an SRIF antagonist with no detectable agonist activity has been identified from a synthetic combinatorial hexapeptide library containing 6.4 × 107 unique
peptides. Each peptide in the library is amino-terminally acetylated
and carboxyl-terminally amidated and consists entirely of
D-amino acids. A SRIF-responsive yeast growth assay was
used as a primary screening tool, and cAMP accumulation, competitive binding, and microphysiometry also were used to confirm and further characterize SRIF antagonist activity. The hexapeptide library was
screened in stepwise iterative fashion to identify AC-178,335, a pure
SRIF antagonist of the sequence Ac-hfirwf-NH2. This
D-hexapeptide bound SRIF receptor type 2 with an
affinity constant (Ki) of
172 ± 12 nM, blocked SRIF inhibition of
adenylate cyclase in vitro (IC50 = 5.1 ± 1.4 µM), and induced GH release when given alone
(50 µg intravenously) to anesthetized rats with or without pretreatment with a long-acting SRIF agonist.
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