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PEPTIDE TRENDS MAY 2020

APELIN

Apelin was discovered as the endogenous ligand of the orphan G protein-coupled receptor APJ in 1998. Apelin is expressed as a 77-amino acid preprotein consisting of the 55-amino acid proapelin fragment and an N-terminal signal sequence. Cleavage of this 22-residue signal peptide produces a 55-residue isoform, apelin-55. Apelin-55 can be further processed to shorter, N-terminally truncated isoforms. The predominant isoforms identified in vivo are apelin-36, -17, -13, named according to the number of C-terminal residues retained. Apelin-13 can undergo cyclization of the glutamine at its N-terminus to produce (Pyr1)-apelin-13 (see Figure 1). In humans, apelin is expressed in various organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues.

 

Figure 1 Sequences of Apelin Peptides.

Adapted from C.Read et al., Pharmacological Review 71, 467-502 (2019)

 

 

Apelin Receptor

The apelin receptor (AR or APJ) is a class A, rhodopsin-like G protein-coupled receptor, which shares closest homology to the angiotensin II type 1 receptor (AT1). Despite this homology, it does not bind angiotensin II.

The human apelin receptor consists of 380 amino acids. It shares a similar tissue distribution with its endogenous ligand apelin indicating that apelin acts as a paracrine/autocrine mediator. Immunocytochemical detection of the human apelin receptor localized it to cardiomyocytes, vascular smooth muscle and endothelial cells.

The apelin receptor is thought to signal primarily through GαI, leading to decreased intracellular cyclic adenosine monophosphate (cAMP) by inhibition of adenylyl cyclase. There is, however, also significant evidence that the apelin receptor may couple to Gαq, particularly in cardiomyocytes to activate phospholipase C (PLC) and protein kinase C (PKC).

In the heart, the apelin receptor may act as a mechanosensor for stretch in an apelin-independent/G protein-independent manner through recruitment of β-arrestin, a protein that initiates receptor internalization as well as downstream signaling.

 

Elabela/Toddler

In 2013 a second endogenous agonist for the apelin receptor, Elabela, was discovered. It was also independently given the name ‘Toddler’ after its identification as a mitogen during gastrulation. Elabela/Toddler is a 54 amino acid peptide, which is encoded by apela. Apela mutant zebrafish exhibit severe developmental defects, including rudimentary or absent heart formation. The studies predicted the existence of three mature Elabela/Toddler peptides with 32, 21 and 11 amino acids.

 

Role of Apelin/APJ in Physiology and Pathophysiology

Apelin and its receptor are implicated in various physiological processes, including the regulation of the cardiovascular system, fluid homeostasis and energy metabolism. There is also evidence that they play a role in conditions such as cardiac failure, cancer, and in metabolic disorders such as diabetes.

Apelin is a potent inotropic agent and vasodilator. Much of the interest in this peptide has focused on the potential therapeutic benefit of targeting the apelin receptor in pulmonary arterial hypertension (PAH) and heart failure (HF).

PAH is a fatal disease characterized by a progressive increase in pulmonary vascular resistance and pressure in the pulmonary circulation. It leads to right ventricular hypertrophy and eventually death from right ventricular failure.

There is evidence that the apelin/APJ axis appears to be important for maintaining pulmonary vascular homeostasis and therefore represents a potential target for PAH therapy. For example, serum apelin levels in PAH patients are significantly lower than those of controls. In mice, disruption of the apelin/APJ system exacerbates hypoxia-induced pulmonary hypertension. In monocrotaline-induced pulmonary hypertension apelin decreases myocardial injury and improves right ventricular function.

Enhancing apelin receptor signaling may also be beneficial in left ventricular HF. In humans, apelin plasma levels are decreased in late-stage HF. Apelin knockout mice develop progressive left ventricular dysfunction associated with aging and severe HF with pressure overload. In animal models of myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries, apelin has been shown to have cardioprotective effects.

 

Fluid Homeostasis

Apelin has been demonstrated to have roles in the uptake and retention of fluid. These responses appear mostly to be through interactions with regions of the central nervous system associated with arginine-vasopressin (AVP). In animal models, experimental data demonstrated that central injection of apelin into lactating rats inhibits the phasic electrical activity of AVP neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing renal blood flow and by counteracting the antidiuretic effect of AVP at the tubular level.

 

Cancer

Apelin/APJ expression is elevated in a number of cancers indicating a potential role of this axis in the development and progression of cancers. Various studies suggest that apelin is involved in the proliferation and growth of tumors. Apelin increases the expression of factors involved in cell proliferation and activates signaling pathways that promote tumor growth and progression. It inhibits tumor cell apoptosis in several cancers and increases tumor stability. In addition, apelin has been identified as an angiogenic factor.

 

Diabetes

Apelin is also implicated in stimulating several metabolic functions such as glucose homeostasis. It inhibits insulin secretion and increases insulin sensitivity. Apelin is found to be increased in obese and type 2 diabetic individuals. The increased plasma apelin observed in type 2 diabetics has been proposed as a compensatory mechanism to directly counteract insulin resistance. In a recent trial, it was demonstrated that apelin administration improved insulin sensitivity in overweight men.

 

Conclusion

The apelin/APJ system is involved in various physiological and pathophysiological processes and therefore represents an attractive target for therapeutic interventions in cardiovascular diseases, cancer and metabolic disorders such as diabetes. Bachem offers a range of readily available apelin peptides and can also support your research with an excellent custom synthesis service.

Table 1 Bachem Apelin Peptides

Product Number Product Name
4038636 Apelin-12 (human, bovine, mouse, rat)
4029109 Apelin-13 (human, bovine, mouse, rat)
4104812 (Pyr¹)-Apelin-13 (human, bovine, mouse, rat) Acetate salt
4029110 (Pyr¹)-Apelin-13 (human, bovine, mouse, rat)
4050032 (Ala¹³)-Apelin-13 (human, bovine, mouse, rat) Trifluoroacetate salt
4095877 (Ala¹³)-Apelin-13 (human, bovine, mouse, rat) Acetate salt
4050029 Apelin-17 (human, bovine, mouse, rat) Trifluoroacetate salt
4034005 Apelin-36 (human)
4086606 Apelin-36 (1-16) amide (human) Trifluoroacetate salt

References

J.Masoumi, A.Jafarzadeh, H.Khorramdelazad, M.Abbasloui, J.Abdolalizadeh, N.Jamali, Role of Apelin/APJ axis in cancer development and progression. Advances in Medical Sciences 2020, 65, 202-213.

C.Read, D.Nyimanu, T.L.Williams, D.J.Huggins, P.Sulentic, R.G.C.Macrae et al, International Union of Basic and Clinical Pharmacology. CVII. Structure and pharmacology of the apelin receptor with a recommendation that Elabela/Toddler is a second endogenous peptide ligand. Pharmacological Reviews 2019, 71, 467-502.

P.Gourdy, L.Cazals, C.Thalamas, A.Sommet, F.Calvas, M.Galitzky et al, Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp. Diabetes, Obesity and Metabolism 2018, 20, 157-164.

M.B.Wysocka, K.Pietraszek-Gremplewicz, D.Nowak, The role of apelin in cardiovascular diseases, Obesity and Cancer. Frontiers in Physiology 2018, 9, 557.

C.Bertrand, P.Valet, I.Castan-Laurell, Apelin and energy metabolism. Frontiers in Physiology 2015, 6, 115.

P.Yang, J.J.Maguire, A.P.Davenport, Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends in Pharmacological Sciences 2015, 36, 560-567.

APELIN IN CLINICAL DEVELOPMENT

Apelin, a ligand of the orphan G protein-coupled receptor APJ, belongs to the family of adipokines. The distribution of apelin and APJ suggests that the apelin/APJ system is involved in a wide range of physiological and pathological processes. For example, the apelin/APJ system plays a role in the regulation of blood pressure, angiogenesis, and energy metabolism in addition to pathological processes such as heart failure, obesity, diabetes and cancer (1). Potential drugs targeting APJ and apelin have garnered interest in many of these areas. At present, there are apelin peptides in preclinical development as shown in Table 1.

Table 1 Apelin Peptides in Development

Product Name Company or Organization Highest Phase Indication
CB5064 analogs CohBar Preclinical Type 2 Diabetes
APJ receptor agonist French National Institute of Health and Medical Research Preclinical Cognitive Disorders
Apelin-13 analogs University of Ulster Preclinical Type 2 Diabetes, Obesity

Preclinical Candidates

CohBar is developing CB5064 analogs for the treatment of type 2 diabetes and other metabolic diseases. CB5064 is a mitochondrially encoded peptide and an agonist of the apelin receptor (1). In June 2019, the company presented a poster on the preclinical data of CB5064 analogs at the American Diabetes Association Scientific Sessions. The studies demonstrated that peptide analogs of CB5064 show agonist activity at the apelin receptor and were effective in body weight reduction and improved glucose tolerance in diet-induced obese (DIO) mice (2).

 

An apelin peptide is under development by the French National Institute of Health and Medical Research for the treatment of postoperative cognitive dysfunction. Research has shown that this apelin receptor agonist reduced pain inflammation and postoperative cognitive impairment in a mouse model of closed tibial fracture (1).

 

The University of Ulster is developing fatty acid analogs of apelin-13 for the treatment of type 2 diabetes and obesity. These analogs act as apelin receptor agonists. In preclinical studies, one of the apelin-13 analogs induced a significant decrease in bodyweight compared to liraglutide (1). In addition, research has shown that the analogs have similar glucose lowering capabilities to GLP-1 but superior lipid lowering effects (3).

 

Conclusion

Synthetic apelin agonists have shown potential as therapeutics for type 2 diabetes, obesity and cognitive impairment. In addition, apelin peptides are of interest in the areas oncology and cardiovascular disease. For organizations and researchers studying the apelin/APJ system, Bachem offers apelin  research peptides. In addition, Bachem offers a custom peptide synthesis service and the production of New Chemical Entities.

 

References

1. M.B.Wysocka, K.Pietraszek-Gremplewicz and D.Nowak. The role of apelin in cardiovascular diseases, obesity and cancer. Frontiers in Physiology 2018, 9, 557.

2. GlobalData 2020.

3. K.Grindstaff et al. Novel analogs of the mitochondrially encoded peptide CB5064 improve body weight and glucose tolerance in DIO mice. ADA 19th Scientific Sessions 2010.

4. O.Lynch, APJ receptor agonists provide for improved metabolic control and weight loss. Ulster University 2014.

MEET BACHEM: ARBER KAMERI, GROUP LEADER MATERIALS STORAGE

PT: Briefly, what do you do at Bachem?

Arber: The technical warehouse is very important in our company. Here we coordinate all material flows of the most different departments in the company. Delivered goods are unloaded, checked, and booked in the system via SAP. A major part of my work is the commissioning of goods based on customer orders and ensure the transport of the goods to their destination.

 

PT: What is your academic background/degrees or training?

Arber: In 2014, I completed the logistics training at Bachem. With the aim to develop my professional skills, I decided to complete further training to become a logistics specialist. Since I like to work with young apprentices, I completed the training as a training officer.

 

PT: What do you like to do outside of work?

Arber: I prefer to spend time with my family. When the weather is fine, I like to go out with friends.

 

PT: What is your business motto?

Arber: Nothing is impossible - there is a solution for everything.

 

PT: What do you like most about your job?

Arber: I love the challenge of changing things in order to contribute to the impressive development of Bachem. As an important interface between many departments, I accept every challenge.

 

PT: Thank you very much Arber.

LITERATURE CITATIONS

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

P.Jaiprasart et al.

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

Oncotarget 11, 99-114 (2020)

 

CS.E.Kwak et al.

Effects of exercise-induced apelin on muscle function and cognitive function in aged mice.

Experimental Gerontology 127, 110710 (2019))

 

G.Mastrella et al.

Targeting APLN/APLNR improves antiangiogenic efficiency and blunts proinvasive side effects of VEGFA/VEGFR2 blockade in glioblastoma.

Cancer Research 79, 2298-2313 (2019)

 

I.Uribesalgo et al.

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.

EMBO Molecular Medicine 11, e9266-e9266 (2019)