CRRL269: a novel designer and renal-enhancing pGC-A peptide activator

Abstract

The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also investigated. In vitro NP receptor activity was quantified with guanosine 3',5'-cyclic monophosphate generation. In vivo effects were determined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldosterone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor.

Particulate Guanylyl Cyclase A/cGMP Signaling Pathway in the Kidney: Physiologic and Therapeutic Indications

“…In bovine adrenal glands and zona glomerulosa cells, ANP activates PDE2 and reduces aldosterone levels generated from adrenal cells and tissues [ 25 , 26 ]. In addition, evidence from animal studies and a human clinical trial clearly supports pGC-A activation in the inhibition of aldosterone levels in vivo [ 27 , 28 ]. Thus pGC-A/cGMP/PDE2 signaling is another pathway involved in promoting water/sodium excretion.…”

“…Optimally, such activators would also possess less hypotensive properties, which has limited the therapeutic use of NPs such as BNP (i.e., nesiritide). Based on selective AA cassettes of BNP and URO, we designed a novel pGC-A activator, CRRL269 that possesses renal-selective properties [ 27 ] ( Figure 2 ). In vitro experiments demonstrated that CRRL269 generated enhanced cGMP in HEK293 cells overexpressing pGC-A receptors and in primary human renal proximal tubular cells compared to native BNP and URO ( Figure 3 ).…”

“…* p < 0.05, versus baseline (1-way ANOVA and Dunnett post-tests), † p < 0.05, versus BNP, # p < 0.05, versus URO (2-way ANOVA and Bonferroni post-hoc tests). American Journal of Physiology-Regulatory, Integrative and Comparative Physiology [ 27 ].…”

Guanylyl Cyclase-cGMP Signaling Pathway in Melanocytes: Differential Effects of Altered Gravity in Non-Metastatic and Metastatic Cells

“…For GC-A as a target, the drugs Carperitide and Nesiritide have been approved for the treatment of congestive HF, and for the chimeric natriuretic peptide CD-NP, positive therapeutic effects in a clinical study have been reported [34,35]. Recently, a novel GC-A activator, CRRL269, was designed, which induces in in vivo experiments an enhanced diuresis, natriuresis, and an increased glomerular filtration rate in comparison with the native GC-A activators BNP and URO [36]. GC-B is the target for drugs in the development of a treatment of skeletal diseases [37].…”

Emerging concepts of receptor endocytosis and concurrent intracellular signaling: Mechanisms of guanylyl cyclase/natriuretic peptide receptor-A activation and trafficking

“…Further, ANP has been shown to exhibit anti-inflammatory properties and tumor-associated immune response [54,55]. Moreover, the synthetic novel designer natriuretic peptides have provided the renal enhancing actions of these hormones over the naturally occurring molecules [56][57][58][59].…”