Chimeric natriuretic peptide ACNP stimulates both natriuretic peptide receptors, the NPRA and NPRB

Here, we investigated the receptor profile of the newly designed natriuretic peptide (NP) ACNP consisting of the N- and C-terminus of human ANP and the ring structure of CNP, its potency/efficacy in stimulating cGMP generation in primary cells, and its stability towards peptidase activity. ACNP stimulated both human natriuretic peptide receptors (NPRs), NPRA and NPRB, as potent as their native ligands in receptor transfected cells. Consequently, ACNP was more efficient in generating cGMP compared to ANP, BNP, and CNP, in primary cells expressing both NPRs. All NPs have been similarly degraded by neprilysin, except the neprilysin-resistant BNP. However, ACNP was fastest degraded in serum, while CNP was most stable. Congruently, CNP but not ACNP reduced blood pressure most significantly after acute peptide infusion in normotensive mice. Our data identify ACNP as the first compound being able to stimulate both natriuretic receptors with similar potency and efficacy as their respective ligands.

► The designed natriuretic peptide ACNP stimulates cGMP generation via NPRA and NPRB.
► Stronger cGMP release by ACNP than ANP or CNP in primary cells having both receptors.
► ACNP is fastest degraded, whereas CNP is most stable in serum of different species.
► Therefore, CNP but not ACNP is most efficient in lowering blood pressure acutely.
► Thus, ACNP requires modification to be superior to its parent peptides in vivo.