Peptide Trends November 2019


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Hypertension is an established risk factor for the development of cardiovascular diseases (CVD), stroke, and kidney diseases.

Hypertension is considered a silent killer as it rarely causes symptoms. According to the WHO, it affects about 1 billion worldwide and is responsible for the deaths of approximately nine million people annually. Hypertension is more prevalent in low- and middle-income countries than in high-income countries and is more common in certain races. According to the WHO, this increase is due mainly to a rise in hypertension risk factors in those populations.

There are several behavioral risk factors for the development of hypertension. These include physical inactivity, poor stress management, harmful levels of alcohol use, high sodium and fat intake and other dietary habits such as not eating enough fruit and vegetables. Genetic factors also contribute to the risk of developing hypertension. People with a family history of hypertension are more likely to develop the condition. In addition, there are several metabolic factors that increase the risk of heart disease, stroke, kidney failure and other complications of hypertension, including diabetes, high cholesterol and obesity.

One can distinguish two different types of hypertension, primary and secondary. Primary hypertension, also referred to as essential hypertension is the most prevalent type and affects 90-95% of hypertensive patients. In contrast to secondary hypertension it does not have a clear etiology.

Secondary hypertension arises from an identifiable cause such as kidney disease or adrenal disease. It can also arise from medication. It is diagnosed in 5-10% of the hypertensive patients.

The treatment of secondary hypertension depends on its cause. First line medications to treat essential hypertension include calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and thiazide diuretics.

 Homeostatic Mechanisms of Blood Pressure Regulation

The body uses several mechanisms to regulate arterial blood pressure in order to ensure adequate blood flow to all organs in the body. These include regulation by baroreceptor reflex, antidiuretic hormone (vasopressin) and the renin-angiotensin-aldosterone system (RAAS).

Baroreceptor Reflex

The baroreceptor reflex enables the body to respond to acute changes in blood pressure detected by baroreceptors located within blood vessels. Baroreceptors are stretch-sensitive mechanoreceptors, which send impulses to the central nervous system and thereby reflexively influence peripheral vascular resistance and cardiac output. Baroreceptors exist in two forms: high pressure arterial baroreceptors in the arterial system and low pressure baroreceptors in large veins, pulmonary vessels, and within the walls of the right atrium and ventricle.


Vasopressin, also known as an antidiuretic hormone, is a nine amino acid peptide secreted from the posterior pituitary. It is synthesized in the hypothalamus and transported via the hypothalamic-hypophyseal tracts to the posterior pituitary where it is stored until released upon nervous stimulation. Vasopressin acts on the kidneys to increase blood volume and by constriction of the blood vessels resulting in increased blood pressure.

Vasopressin is released in response to triggers such as low blood pressure monitored by high-pressure baroreceptors, high serum osmolarity, low blood volume and increased plasma levels of angiotensin II.

Renin-Angiotensin-Aldosterone System (RAAS)

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of arterial pressure and plays a key role in the pathogenesis of essential hypertension. It is composed of three major compounds: renin, angiotensin II, and aldosterone.

Renin is the initiative enzyme for the renin-angiotensin system. It is expressed in the juxtaglomerular cells of the kidney and secreted into the circulation in response to decreased renal blood pressure, decreased salt delivery to the distal convoluted tubules of the nephrons, and/or β-agonism. Once released, plasma renin acts on angiotensinogen and cleaves it into angiotensin I, the inactive precursor of angiotensin II. Subsequent cleavage of angiotensin I by ACE yields angiotensin II (Figure 1). Angiotensin II functions in many ways to increase arterial pressure including vasoconstriction of arterioles by binding to AT1 receptors, release of vasopressin from the posterior pituitary and release of aldosterone from the adrenal cortex.

Aldosterone causes the distal convoluted tubules to increase reabsorption of sodium and to increase secretion of potassium. The increase in sodium reabsorption leads to passive reabsorption of water and an increase in blood pressure.

 Angiotensin II can be further processed by ACE2 to yield angiotensin 1-7. In contrast to angiotensin II, this fragment acts on the G protein-coupled receptor Mas1 and initiates a counter-regulatory role by opposing angiotensin II induced vasoconstriction.

 ACE can also hydrolyze and inactivate bradykinin leading to attenuation of the vasodilatory function of bradykinin.

 Food-derived Antihypertensive Peptides

Many food-derived proteins contain antihypertensive peptides encrypted in their protein sequences. They can be released during gastrointestinal transit or by food processing such as enzymatic hydrolysis or fermentation.

Antihypertensive sequences have been identified from many animal sources but also from a variety of plants, fungi and algae.

In many cases, the antihypertensive effect is mediated through inhibition of ACE (Figure 1). In the literature, numerous ACE inhibitory peptide sequences have been described including sequences isolated from dairy products, egg, meat, fish and plant proteins. The identified peptides often show various activities related to blood pressure regulation.


Figure 1 Common Inhibitory Routes of Antihypertensive Peptides
(AHP: Antihypertensive Peptides; AT1: Angiotensin Receptor 1; AT2: Angiotensin Receptor 2; MAS1 Mas 1 Receptor)
Adapted from A.Iwaniak et al., Food-originating ACE inhibitors, including antihypertensive peptides, as preventive food components in blood pressure reduction. Comprehensive Reviews in Food Science and Food Safety 13, 114-134 (2014)


ACE Inhibitory Peptides

The most commonly known peptides of milk origin exhibiting ACE inhibitory activity are VPP and IPP. They are present in β-casein and κ-casein, respectively. Both peptides are ingredients of nutraceutical antihypertensive drinks available for example in Japan and Finland.

β-casomorphin 7 (YPFPGPI), another casein peptide derived from the A1 or B β-casein variant was shown to inhibit ACE enzyme activity. In addition, it displayed immunomodulatory effects.

Other examples of milk protein-derived peptides with ACE inhibitor activity are VAP, FALPQY and VTSTAV from casein, WLAHK, ALPMHIR and ALKAWSVAR from whey, and LIWKL, RPYL and LNNSRAP from lactoferrin, a member of the transferrin family of iron-binding glycoproteins.

Many ACE inhibitory peptide sequences have also been isolated from avian egg white proteins. These include sequences as YAEERYOIL, RADHPFL, IVF, FRADHPFL and LW.

In addition to ACE inhibitory sequences derived from animal proteins, many of these peptides have also been found in plants. Common sources for antihypertensive plant peptides are soybean, mung bean, rice, wheat, and spinach. Some examples are given below.

Peptidic fractions derived from peptic digests of soybean were tested positive for ACE inhibitory activity. Oral administration of peptidic fractions also markedly lowered the blood pressure of spontaneously hypertensive rats (SHRs). Further separation of the peptidic fractions by HPLC revealed several active peptides: IA, YLAGNQ, IYLL, and VMDKPQG.

Mung bean proteins are an additional source for ACE inhibitors. Alcalase hydrolysates of this plant also contained activities against ACE. Purification of the ACE inhibitory peptides led to the identification of the peptide fragments KDYRL, VTPALR and KLPAGTLF.

An ACE inhibitory peptide was also detected in alcalase hydrolysates of rice. The isolated peptide sequence TQVY also showed antihypertensive activity in vivo.

Studies with spinach pepsin-pancreatin digests of RuBisCo (ribulose-1,5-bisphosphate carboxylase) led to the discovery of MRWRD, MRW, LRIPVA, and IAYKPAG. All three peptides exhibited ACE inhibitory activity and reduced blood pressure in the SHR animal model.

Other Mechanisms

In addition to the effects on ACE activity, antihypertensive peptides can interact with renin, endothelin-converting enzyme (ECE), angiotensin receptors, calcium channels, and opioid receptors and play a role on the endothelin system function, arginine-nitric oxide pathway, and vascular remodeling.

For example, the dipeptides IA, KF and EF from thermolysin-hydrolized pea proteins showed strong inhibitory properties not only towards ACE and but also towards renin. In another study, four novel peptide sequences (WVYY, WYT, SVYT, and IPAGV) were identified from an enzymatic digest of hemp seed proteins, which also interacted with the active site of renin. WVYY was a more potent ACE-inhibitory peptide than WYT. WYT and SVYT had similar renin-inhibitory activity, which was significantly better than that of IPAGV.

Some milk lactoferrin-derived peptides (LIWKL, RPYL, and RRWQWR) have been shown to inhibit angiotensin II-induced vasoconstriction. Among these peptide RPYL exhibited the highest ex vivo inhibitory effect and also inhibited binding of [(125)I]-(Sar(1),Ile(8))-angiotensin II to AT1 receptors. These effects were reported to be selective for the AT1 receptors as the endothelin-1 receptor-mediated vasoconstriction was not inhibited by the peptide. Therefore, inhibition of angiotensin II-induced vasoconstriction has been suggested as a mechanism contributing along with ACE inhibition to the antihypertensive effect of some lactoferrin-derived peptides.

It could be demonstrated that some food-derived peptides interfere with the endothelin system. They were shown to inhibit ECE, which induces a wide range of physiological effects including vasoconstriction. For example, pepsin digests of bonito pyrolic appendix and beef showed ECE inhibitory activities. Pronase treatment resulted in the disappearance of the ECE inhibitory activities indicating that peptides were responsible for these inhibitory activities.

In another study, two peptides selected from proteinase K hydrolysates of bovine lactoferrin were chemically synthesized. Both peptides, GILRPY and REPYFGY, exerted in vitro inhibitory effects on ECE activity.

Peptides derived from fish protein hydrolysate have shown antihypertensive effects by blocking Ca2+ channels. Blocking of voltage-dependent calcium channels can reduce Ca2+ influx into vascular muscle cells and thereby suppress vasoconstriction.

Food-derived peptides can also interfere with the arginine-nitric oxide pathway. Bradykinin is a key component of the kallikrein-kinin system. It mediates a signaling process that results in the activation of the endothelial nitric oxide synthase (eNOS), which catalyzes the conversion of arginine to the potent vasodilator nitric oxide (NO) and citrulline. α-lactorphin, YGLF, and β-lactorphin, YLLF, have been suggested to mediate the endothelium-dependent vasorelaxation effects by binding to endothelial opioid receptors and subsequent NO release.


Antihypertensive peptides from food proteins have been studied for decades. Numerous peptides have been identified and studied in vitro and often also in vivo. A large number of these peptide sequences act by inhibition of ACE, a key enzyme in blood pressure regulation, which is also the target of many common antihypertensive drugs. However, many antihypertensive peptides mediate their effects by mechanisms different to ACE inhibition or exhibit effects on other regulators of blood pressure.

Antihypertensive peptides have gained considerable interest as nutraceutical ingredients in functional food and potentially have a positive influence on blood pressure. However, for efficient blood pressure reduction antihypertensive drugs so far remain indispensable.

Bachem offers a number of readily available synthetic antihypertensive peptides (s. Table 1) and can also support your research with an excellent custom synthesis service. 

Product NumberOne Letter CodeProduct Description
4006342AWThe dipeptide AW is a non-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 6.4 μM.
4005177AYInhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 14.2 μM. Ala-Tyr has been used as a tyrosine source in intravenous nutrition of the rat. The dipeptide AY is an efficient Tyr source for the parenteral nutrition of patients with hepatic failure.
4007920GGYThe tripeptide GGY showed ACE-inhibitory activity, IC₅₀ 1.3 µmol/l.
4016786IRPThe tripeptide IRP showed ACE-inhibitory activity, IC₅₀ 1.8 µmol/l.
4029177IPPAntihypertensive tripeptide originally isolated from fermented milk. IPP inhibited angiotensin I-converting enzyme (ACE) with an IC₅₀ of 5 µM.
4001989IWIW, non-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 4.7 μM.
4002273IYPotent dipeptide angiotensin I-converting enzyme (ACE) inhibitor, IC₅₀ 0.008 mg/ml. Application of IY reduced blood pressure in spontaneously hypertensive rats.
4000861LAPThe tripeptide LAP showed ACE-inhibitory activity, IC₅₀ 3.5 μmol.
4016954LGPThe tripeptide LGP showed ACE-inhibitory activity, IC₅₀ 0.7 mmol/l.
4041904LPPThe proline-rich tripeptide LPP showed ACE-inhibiting activity as IPP (H-4632) and VPP (H-4634), IC₅₀ 9.6 µM.
4030830LWLW is an ACE-inhibitory dipeptide found in fermented milk, IC₅₀ 6.6 μM. Substrate for aminopeptidase W, Km 0.57 mM and kcat 6770 min⁻¹.
4005237FWFW, a highly potent ACE inhibitor, can also form nanotubes.
4000110MWNon-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 9.8 μM.
4006116PRPR inhibited angiotensin-1 converting enzyme (ACE), IC₅₀ 4.1 μM.
4001974PFSubstrate for human kidney prolinase (prolyl dipeptidase). ACE2 inhibitor, IC₅₀ 0.15 mM.
4002549YLA dipeptide from β-lactoglobulin showing ACE-inhibitory activity, IC₅₀ 122.1 μmol.
4001995VFVal-Phe inhibited angiotensin-1 converting enzyme (ACE), IC₅₀ 9.2 μM. Contrary to the dipeptide Ile-Phe (G-2420) containing merely an additional methyl group, Val-Phe does not self-assemble.
4038134VPPAntihypertensive tripeptide originally isolated from fermented milk. VPP inhibited angiotensin I-converting enzyme (ACE) with an IC₅₀ value of 9 µM.
4008196VWThe dipeptide Val-Trp is a potent, competitive dipeptide angiotensin I-converting enzyme inhibitor with a Ki of 0.3 µM. Dipeptide-2 is a component of various cosmetic formulations, e.g. for anti-wrinkle and anti-aging cosmetics.
4001976VYAntihypertensive dipeptide. Acts as ACE inhibitor, IC₅₀ 0.02 mg/ml. G-3585 showed an antihypertensive effect when administered orally to spontaneously hypertensive rats for 28 days.


J.S.Shahoud, N.R.Aeddula, Physiology, Arterial pressure regulation. StatPearls: Treasure Island (FL), 2019.

L.Wahl, R.S.Tubbs, A review of the clinical anatomy of hypertension. Clinical anatomy 2019, 32, 678-681.

B.Miralles, L.Amigo, I.Recio, Critical review and perspectives on food-derived antihypertensive peptides. Journal of Agricultural and Food Chemistry 2018, 66, 9384-9390.

R.E.Aluko, Antihypertensive peptides from food proteins. Annual Review of Food Science and Technology 2015, 6, 235-262.

A.Iwaniak, P.Minkiewicz, M.Darewicz, Food-originating ACE inhibitors, including antihypertensive peptides, as preventive food components in blood pressure reduction. Comprehensive Reviews in Food Science and Food Safety 2014, 13, 114-134.

A.T.Girgih, R.He, R.E.Aluko, Kinetics and molecular docking studies of the inhibitions of angiotensin converting enzyme and renin activities by hemp seed (Cannabis sativa L.) peptides. Journal of Agricultural and Food Chemistry 2014, 62, 4135-4144.

K.Majumder, J.Wu, Molecular targets of antihypertensive peptides: understanding the mechanisms of action based on the pathophysiology of hypertension. International journal of molecular sciences 2014, 16, 256-283.

C.C.Udenigwe, A.Mohan, Mechanisms of food protein-derived antihypertensive peptides other than ACE inhibition. Journal of Functional Foods 2014, 8, 45-52.

R.Fernandez-Musoles, J.B.Salom, D.Martinez-Maqueda, J.J.Lopez-Diez, I.Recio, P.Manzanares, Antihypertensive effects of lactoferrin hydrolyzates: Inhibition of angiotensin- and endothelin-converting enzymes. Food Chemistry 2013, 139, 994-1000.

WHO, A global brief on hypertension. 2013.

K.Sawicka, M.Szczyrek, I.Jastrzębska, M.Prasał, A.Zwolak, J.Daniluk, Hypertension – The silent killer. Journal of Pre-Clinical and Clinical Research 2011, 5, 43-46.

H.Li, R.E.Aluko, Identification and inhibitory properties of multifunctional peptides from pea protein hydrolysate. Journal of Agricultural and Food Chemistry 2010, 58, 11471-11476.

H.Kayser, H.Meisel, Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins. FEBS letters 1996, 383, 18-20.




Hypertension, or high blood pressure, affects an estimated 1.13 billion people worldwide (1). A healthy diet is known to play a key role in the prevention of hypertension and cardiovascular disease. Peptides with antihypertensive properties are available from common food protein sources such as milk, eggs, fish, meat and some plant-based sources. Many food-derived peptides act by inhibiting angiotensin-converting enzyme (ACE) or renin (2). There are commercial food, beverage and dietary supplements that provide antihypertensive peptides such as the Japanese dairy-based soft drink Calpis®, the bonito fish peptide supplement called Vasotensin®, and the sardine peptide Valtyron®. Some food-derived peptides have been studied in human clinical trials. Table 1 shows antihypertensive peptide food sources that are currently in planned or ongoing clinical trials.

Food Source/Intervention(s)Trial PhaseTrial Phase Sponsor
Hemp seed protein and hemp seed protein hydrolysate derived bioactive peptides, hemp seed protein, casein proteinNot applicableUniversity of Manitoba, Richardson Centre for functional Foods and Nutraceuticals
FlaxseedPhase 2St. Boniface General Hospital Research Centre; Canadian Institutes of Health Research

Hemp Seed

Hemp seeds are a source of plant-based protein. The University of Manitoba is studying the effect of hemp seed protein, hemp seed protein with hydrolysate derived bioactive peptides and casein protein consumption on systolic and diastolic ambulatory blood pressure. The primary outcome measure of the study is the change in 24 hour ambulatory blood pressure (3).


Flaxseed, or linseed, is rich in nutrients such as fiber, proteins and vitamins. St. Boniface General Hospital Research Center is studying flaxseed in a clinical trial to determine the efficacy of daily consumption of flaxseed on the reduction of blood pressure in hypertensive patients who were recently diagnosed and have not yet received anti-hypertensive drugs. Trial participants are given either the control or flaxseed containing foods items such as muffins, bagels and milled flaxseed (4).


There is interest in the use of natural food based products to prevent and treat hypertension. In the future, new clinical studies are anticipated to show how various food-derived peptides can contribute to blood pressure control and provide other health benefits. For researchers interested in hypertension, Bachem offers a selection of antihypertensive peptides as catalog products. Bachem also offers a custom peptide synthesis service and the production of New Chemical Entities.


(1) Hypertension. World Health Organization (2019)

(2) A.Iwaniak et al., Food-originating ACE inhibitors, including antihypertensive peptides, as preventive food components in blood pressure reduction. Comprehensive Reviews in Food Science and Food Safety, 13, 114-134 (2014)

(3) Double blind, randomized, cross over trial of whole hemp seed protein and hemp seed protein hydrolysate derived bioactive peptide consumption for hypertension, (2018)

(4) The efficacy of dietary flaxseed for the reduction of blood pressure in newly diagnosed hypertensive individuals, (2013)


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Peptide highlights

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Strangling cancer with a vaccine made of wrongly coded proteins-FierceBiotech