Cenderitide (also known as chimeric natriuretic peptide or CD-NP) is a

natriuretic peptide A natriuretic peptide is a peptide that induces natriuresis, which is the excretion of sodium by the kidneys. Known natriuretic peptides include the following: * atrial natriuretic peptide, also known as ANP * brain natriuretic peptide, also known ...

developed by the

Mayo Clinic The Mayo Clinic () is a nonprofit American academic medical center focused on integrated health care, education, and research. It employs over 4,500 physicians and scientists, along with another 58,400 administrative and allied health staff, ...

as a potential treatment for

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

. Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom

dendroaspis natriuretic peptide Dendroaspis natriuretic peptide (DNP) is a 38-residue peptide and a member of natriuretic peptide family. It is structurally similar to the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) and p ...

(DNP) with the full

C-type natriuretic peptide Natriuretic peptide precursor C, also known as NPPC, is a protein that in humans is encoded by the ''NPPC'' gene. The precursor NPPC protein is cleaved to the 22 amino acid peptide C-type natriuretic peptide (''CNP''). Function Natriuretic pe ...

(CNP) structure. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the

natriuretic Natriuresis is the process of sodium excretion in the urine through the action of the kidneys. It is promoted by ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldosterone. Natriuresis lowers ...

and

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.

Molecular problem: fibrosis

When faced with pressure overload, the heart attempts to compensate with a number of structural alterations including

hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J ...

of cardiomyocytes and increase of extracellular matrix (ECM) proteins. Rapid accumulation of ECM proteins causes excessive

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

resulting in decreased myocardial compliance and increased myocardial stiffness. The exact mechanisms involved in excessive fibrosis are not fully understood but there is evidence that supports involvement from local growth factors

FGF-2 Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

and platelet-derived growth factor. TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy. The increase in

TGF-beta 1 Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

expression in a pressure-overloaded heart correlates with the degree of fibrosis, suggesting TGF-beta 1 involvement in the progression from a compensated hypertrophy to failure. Through an autocrine mechanism, TGF-beta 1 acts on

fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

s by binding TGF-beta 1 receptors 1 and 2. Upon receptor activation, the receptor-associated transcription factor Smad becomes

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

and associates with Co-Smad. This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression. Cardiac remodelling of the ECM is also regulated by the CNP/NPR-B pathway as demonstrated by the improved outcomes in

transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

mice with CNP over-expression subjected to myocardial infarction. Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP. Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to

. Thus, anti-fibrotic strategies are a promising approach in the prevention and treatment of

Molecular mechanism

As cenderitide interacts with both NRP-A and NRP-B, this drug has antifibrotic potential. Binding of cenderitide to NRP-B elicits an antifibrotic response by catalyzing formation of cGMP similar to the response seen with endogenous CNP. Additionally, ''in vitro'' study of human fibroblasts demonstrates that cenderitide reduces

induced

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

production. These two proposed mechanisms illustrate therapeutic potential for the reduction of fibrotic remodelling in the

hypertensive Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

heart. Through combined effects of CNP and DNP, cenderitide treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodeling pathways.

References

{{Reflist Drugs acting on the cardiovascular system Peptides Experimental drugs