The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. part 1

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Abstract

The cyclic peptide ANP 4-23 and the linear peptide analogue AP-811 have been shown to be selective ANP-CR antagonists. Via alanine scanning and truncation studies we sought to determine which residues in these molecules were important in their binding to the clearance receptor and the relationship between these two molecules. These studies show that several modifications to these compounds are possible which improve physical properties of these molecules while retaining high affinity for the ANP-CR.

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    The most consistent homology between species for Ostn lies in the C-terminal region of the protein, and it is this region that displays homology to the NPs. Most interestingly, the best conserved homology with the NPs includes the residues Phe7, Gly8, and Arg13 (numbering according to CNP) that have been demonstrated to be necessary for peptide binding to the NPR-C receptor (26-28). Furthermore, the lack of the two cysteine residues present in all NPs indicates Ostn does not form the cyclic ring structure that is essential for binding to the receptors signaling through cGMP, GC-A, and GC-B (29, 30).

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    For competition experiments, [125I]-ANP(3–28) was used for NPR-C and GC-A, and [125I]-CNP was used for GC-B experiments. In membranes from CHO-K1 cells expressing human recombinant GC-A receptor, the endogenous natriuretic peptide ANP displaced bound radioligand with characteristic potency (Fig. 1), while GC-B-selective CNP and the NPR-C-selective ligand AP-811 [16] did not displace [125I]-ANP(3–28) (Fig. 1). DNP displaced [125I]-ANP(3–28) with a Ki of 100 pmol l−1 (Fig. 1).

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