B-type natriuretic peptide (BNP) decreases cardiac preload and
hypertrophy. As such, synthetic BNP,
nesiritide, was approved for the treatment of acutely decompensated
heart failure. However, two problems limit its therapeutic potential. First, ensuing
hypertension decreases urine output, and second,
guanylyl cyclase-A (GC-A), the primary signaling receptor for BNP, is down-regulated in
heart failure. Thus, alternative or chimeric
natriuretic peptides maintaining the renal but lacking the vasorelaxation properties of BNP provide an alternative approach. Here, we examined the ability of single amino acid substitutions in the conserved 17-amino
acid disulfide ring structure of human BNP to activate GC-A and
guanylyl cyclase-B (GC-B), which is not reduced in
heart failure. We hypothesized that substitution of highly conserved residues in BNP with highly conserved residues from a GC-B-specific
peptide would yield BNP variants with increased and decreased potency for human GC-B and GC-A, respectively. Substitution of Leu for Arg13 (l-bnp) yielded a 5-fold more potent activator of GC-B and 7-fold less potent activator of GC-A compared with wild type. l-bnp also bound GC-A 4.5-fold less tightly than wild type. In contrast, substitution of Met for Ser21 (M-BNP) had no effect. A
peptide containing both the Leu and Met substitutions behaved similarly to l-bnp. Meanwhile, wild-type and l-bnp bound the
natriuretic peptide clearance receptor with similar affinities. These data indicate that Arg13 of BNP is a critical discriminator of binding to
guanylyl cyclase-linked but not clearance
natriuretic peptide receptors, supporting designer
natriuretic peptides as an alternative to wild-type BNP for the treatment of
heart failure.