Biomedicine & Pharmacotherapy

Biography

Biography: R Manjunatha Kini

Abstract

Natriuretic peptides (NPs) are potent vasoactive hormones, which maintain pressure-volume homoeostasis. All three isoforms of mammalian NPs, namely ANP, BNP and CNP have a conserved 17-residue ring but with highly variable C-terminal extensions. These peptides confer their functions through binding to three membrane-bound NP receptors (NPRs). ANP and BNP bind to NPR-A, whereas CNP binds to NPR-B, both Guanylyl Cyclase (GC) linked receptors. NPR-A and NPR-B undergo conformational change upon respective NP binding and lead to the production of intracellular cGMP. Snake venom NPs, although have the conserved NP-ring, exhibit distinct biological activity compared with mammalian NPs due to subtle changes in their sequences. We recently identified a new NP from Krait Venom (KNP), with an unusual 38-residue long C-terminal tail, which has a propensity to form a α-helix. Deletion mutant studies have revealed the presence of two pharmacophores in KNP, namely ring and helix. These functional segments induced vasodilation through orthogonal pathways. Ring, like a classical NP, elevates intracellular cGMP levels through activation of NPR-A with a 10-fold lower potency compared to ANP, while helix uses NO-dependent mechanisms. By systematic structure-function studies, we were able to delineate the amino acid residues that determine vasodilatory and diuretic functions. Using the new knowledge, development of two classes of human Natriuretic Peptide Analogues (NPAs); one group of NPAs with only vasodilatory effects without diuretic function and the second group with only diuretic effects without vasodilatory function was done. Such distinct classes of NPAs will be useful in the treatment of distinct classes of ADHF (Acute Decompensated Heart Failure) patients.