Global Rise of Heart Failure
Heart failure (HF) is a severe clinical syndrome with an estimated global prevalence of 1-3% [1]. It is characterized by high morbidity and mortality and represents the end-stage manifestation of many cardiovascular diseases. The prevalence of heart failure continues to rise, with an approximate 29% increase between 2010 and 2019. This contributes a significant economic burden of approximately $346.17 billion globally [2].
Figure 1. Global prevalence of heart failure from the past decade across different global regions with available epidemiological data [1].
Clinically, medications used to treat heart failure include diuretics, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), aldosterone receptor antagonists, β-blockers, and cardiac glycosides. ARNIs have shown some improvement in patients' symptoms and quality of life. However, their effects on repairing damaged myocardium and treating severe heart failure are limited, and they may also have side effects. As a result, there remains a significant unmet therapeutic need in the field of heart failure, driving drug development to explore new strategies.
The role of NPR1 in cardiac homeostasis and its relationship with heart disease
NPR1 (Natriuretic Peptide Receptor 1), also known as natriuretic peptide receptor A (NPR-A), is a guanylyl cyclase that is highly abundant in the kidneys, adrenal glands, lungs, terminal ileum, aorta, and adipose tissue. It functions as a dimer and can be activated by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).
NPR1 consists of an extracellular ligand-binding domain, a transmembrane domain, an intracellular particulate guanylyl cyclase (GC) domain, and an intracellular cGMP-dependent protein kinase (PKG) domain. Upon activation, NPR1 catalyzes the conversion of GTP into cGMP. As an intracellular second messenger, cGMP regulates various pathways by activating PKG and phosphodiesterases (PDEs), influencing ion channels, protein phosphorylation, nuclear translocation, and gene expression.
Figure 2. Natriuretic peptide receptor (NPR) structure [3].
The ANP/BNP-NPR1 system primarily functions in the heart by regulating cardiovascular homeostasis and influencing both physiological and pathological states of the heart. It also plays a crucial role in maintaining renal and endocrine homeostasis. Additionally, this system can protect the maternal heart from IL-6-induced inflammation during the perinatal period.
Figure 3. Clinical significance of the cardiac natriuretic peptide system and its clearance system [4].
NPR1 dysfunction is associated with the pathogenesis of heart failure. Studies have shown that NPR1 expression is significantly reduced in patients with heart failure and is correlated with impaired cardiac function. In rat models of heart failure, decreased NPR1 expression is linked to the deterioration of cardiac function indicators, while NPR1 knockout mice exhibit symptoms of impaired cardiac function, such as reduced left ventricular systolic function. NPR1 is a potential therapeutic target for heart failure, offering new treatment options for patients.
Development of NPR1 Agonists
NPR1 agonists are being studied as a novel class of drugs for the treatment of heart failure. Their mechanism of action involves activating NPR1 to promote the synthesis of cyclic guanosine monophosphate (cGMP), which exerts effects such as diuresis and vasodilation, leading to reduced blood pressure and alleviated cardiac workload.
XXB750, developed by Novartis, is an IgG1-type NPR1 agonist. Compared to ARNIs, XXB750 directly mimics the activation mechanism of ANP/BNP on NPR1, bypassing the RAAS (renin-angiotensin-aldosterone system), and has a longer duration of action (lasting over three months after a single subcutaneous injection), significantly improving patient compliance. Additionally, results from the first human clinical trial of XXB750 showed that the drug is generally safe, well-tolerated, and can significantly increase plasma cGMP levels and lower blood pressure, demonstrating its potential as a novel antihypertensive therapy, particularly for Heart Failure with Reduced Ejection Fraction (HFrEF). Currently, XXB750 is undergoing Phase II clinical trials.
Another clinical drug is REGN5381, developed by Regeneron, which utilizes an allosteric activation design. It can activate NPR1 without the presence of natural ligands, continuously lowering blood pressure, with enhanced effects when ANP or BNP is present (Figure 4). This offers a promising direction for long-acting treatment of heart failure.
Figure 4. Mechanism of Action of REGN5381 [5].
REGN5381 is administered via intravenous infusion. At the highest dose (100 mg) in healthy subjects, it reduced systolic blood pressure by 6-9 mmHg, with effects lasting up to 72 hours. Additionally, it showed no significant diuretic effects, demonstrating good safety and tolerability (Figure 5).
Figure 5. Effects of REGN5381 in Healthy Subjects [6].
There is still a significant gap in the development of NPR1 agonists. However, with continued research and investment, more effective NPR1 drugs are likely to emerge in the future.
High-Quality Recombinant NPR1 Proteins
NPR1 offers a new therapeutic strategy for heart failure and holds potential development value in hypertension and kidney disease. KACTUS follows advancements in cardiovascular disease therapeutics and has developed a series of high-quality recombinant NPR1 proteins suitable for the development of NPR1-targeted drugs.
Product Validation Data
Figure 7. Immobilized Human NPR1, His Tag at 5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-NPR1 Antibody, hFc Tag with the EC50 of 26.9 ng/ml determined by ELISA (QC test).
Figure 8. Immobilized Human NPR1, mFc Tag at 5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-NPR1 Antibody, hFc Tag with the EC50 of 21.6 ng/ml determined by ELISA (QC test).
Recombinant NPR1 Proteins Product List
|
Catalog Number |
Product Name |
References
[1] Khan MS, Shahid I, Bennis A, Rakisheva A, Metra M, Butler J. Global epidemiology of heart failure. Nat Rev Cardiol. 2024 Jun 26. doi: 10.1038/s41569-024-01046-6.
[2] Lippi, G., & Sanchis-Gomar, F. (2020). Global epidemiology and future trends of heart failure. AME Medical Journal, 5, Article 15. https://doi.org/10.21037/amj.2020.03.03
[3] Goetze JP, Bruneau BG, Ramos HR, Ogawa T, de Bold MK, de Bold AJ. Cardiac natriuretic peptides. Nat Rev Cardiol. 2020 Nov;17(11):698-717. doi: 10.1038/s41569-020-0381-0.
[4] Bekele AT. Natriuretic Peptide Receptors (NPRs) as a Potential Target for the Treatment of Heart Failure. Curr Heart Fail Rep. 2023 Oct;20(5):429-440. doi: 10.1007/s11897-023-00628-8.
[5] https://doi.org/10.1038/d41573-024-00151-y.
[6] Dunn, M. E., Kithcart, A., Kim, J. H., Ho, A. J., Franklin, M. C., Romero Hernandez, A., De Hoon, J., Botermans, W., Meyer, J., Jin, X., Zhang, D., Torello, J., Jasewicz, D., Kamat, V., Garnova, E., Liu, N., Rosconi, M., Pan, H., Karnik, S., . . . Morton, L. (2024). Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone. Nature, 633(8030), 654-661. https://doi.org/10.1038/s41586-024-07903-1
