C53: A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts

Abstract

The native particulate guanylyl cyclase B receptor (pGC-B) activator, C-type natriuretic peptide (CNP), induces anti-remodeling actions in the heart and kidney through the generation of the second messenger 3',5' cyclic guanosine monophosphate (cGMP). Indeed fibrotic remodeling, particularly in cardiorenal disease states, contributes to disease progression and thus, has been a key target for drug discovery and development. Although the pGC-B/cGMP system has been perceived as a promising anti-fibrotic pathway, its therapeutic potential is limited due to the rapid degradation and catabolism of CNP by neprilysin (NEP) and natriuretic peptide clearance receptor (NPRC). The goal of this study was to bioengineer and test in vitro and in vivo a novel pGC-B activator, C53. Here we established that C53 selectively generates cGMP via the pGC-B receptor and is highly resistant to NEP and has less interaction with NPRC in vitro. Furthermore in vivo, C53 had enhanced cGMP-generating actions that paralleled elevated plasma CNP-like levels, thus indicating a longer circulating half-life compared to CNP. Importantly in human cardiac fibroblasts (HCFs) and renal fibroblasts (HRFs), C53 exerted robust cGMP-generating actions, inhibited TGFβ−1 stimulated HCFs and HRFs proliferation chronically and suppressed the differentiation of HCFs and HRFs to myofibroblasts. The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. Future studies are warranted to explore the efficacy and therapeutic opportunity of C53 targeting fibrosis in cardiorenal disease states and beyond.

C-Type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature

“…However, NPR-B heterozygote mice are susceptible to aortic stenosis [148], suggesting that the importance of this NPR subtype might sit outside the cardiomyocyte. This does not mean that NPR-B cannot be targeted pharmacologically, as recent studies suggest that novel designer peptides that bind to NPR-B can reduce fibroblast proliferation and collagen secretion in vitro and in vivo [128,149,150]. This role of endogenous NPR-C signalling in regulating fibrosis is supported by other studies that have observed greater cardiac dysfunction, atrial collagen deposition, and higher levels of TGFβ and TIMP1 in NPR-C KO mice subjected to angiotensin II-induced pressure overload [151,152].…”

Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor

“…2A). We further treated a pool of plasma samples with neuraminidase to remove only terminal sialic acid residues, followed by immunoprecipitation and detection using pAb proANP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] , and this resulted in a mobility shift of the slower migrating 14 kDa band by ϳ1-2 kDa (Fig. 2B).…”

“…Anesthesia in rats was induced with 133 mg/kg intraperitoneal inactin (Sigma), and rats were maintained on a heating pad for 1 h until complete anesthesia was achieved. With oxygen flow, the rats were then subjected to catherizations and blood and urine collections (2). A polyethylene (PE)-50 tube catheter was placed into the jugular vein for intravenous (i.v.)…”

“…The natriuretic peptide (NP) 3 family comprises atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), which are peptide hormones involved in maintaining cardiorenal homeostasis. The cardiac NPs, ANP and BNP, possess potent diuretic and natriuretic effects as well as blood pressure-lowering properties that are mediated through the natriuretic peptide receptor A (NPR-A), whereas CNP is a potent anti-fibrotic and anti-remodeling factor acting through natriuretic peptide receptor B (NPR-B) (1)(2)(3)(4)(5). All three NPs are synthesized as prohormones and subsequently proteolytically activated by the proprotein convertases corin and furin to form mature receptor-binding peptide hormones.…”

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

“…The addition of neprilysin inhibition provides modulatory effect on endogenous vasoactive peptides such as natriuretic peptides and bradykinin, resulting in beneficial remodelling and vasodilation (D'Elia et al, 2017). Given the therapeutic success of sacubitril–valsartan via natriuretic peptide augmentation, designer natriuretic peptide analogues such as MANP (also known as ZD100) (McKie et al, 2014), CRRL‐269 (Chen, Harty, et al, 2019), NPA7 (Meems et al, 2019), C53 (Chen et al, 2019) or cenderitide (also known as CD‐NP) (Kawakami et al, 2018) may offer an alternative, yet complementary, therapeutic strategy for cardiorenal syndrome and are currently under advanced preclinical and clinical development. Empagliflozin and canagliflozin, sodium‐glucose cotransporter 2 (SGLT2) inhibitors, demonstrated beneficial cardiovascular and all‐cause mortality and hospitalization in diabetic patients with high cardiovascular risk (Zinman et al, 2015).…”