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ANTIHYPERTENSIVE FOOD-DERIVED PEPTIDES
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.
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 Number||One Letter Code||Product Description|
|4006342||AW||The dipeptide AW is a non-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 6.4 μM.|
|4005177||AY||Inhibitor 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.|
|4007920||GGY||The tripeptide GGY showed ACE-inhibitory activity, IC₅₀ 1.3 µmol/l.|
|4016786||IRP||The tripeptide IRP showed ACE-inhibitory activity, IC₅₀ 1.8 µmol/l.|
|4029177||IPP||Antihypertensive tripeptide originally isolated from fermented milk. IPP inhibited angiotensin I-converting enzyme (ACE) with an IC₅₀ of 5 µM.|
|4001989||IW||IW, non-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 4.7 μM.|
|4002273||IY||Potent dipeptide angiotensin I-converting enzyme (ACE) inhibitor, IC₅₀ 0.008 mg/ml. Application of IY reduced blood pressure in spontaneously hypertensive rats.|
|4000861||LAP||The tripeptide LAP showed ACE-inhibitory activity, IC₅₀ 3.5 μmol.|
|4016954||LGP||The tripeptide LGP showed ACE-inhibitory activity, IC₅₀ 0.7 mmol/l.|
|4041904||LPP||The proline-rich tripeptide LPP showed ACE-inhibiting activity as IPP (H-4632) and VPP (H-4634), IC₅₀ 9.6 µM.|
|4030830||LW||LW 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.|
|4005237||FW||FW, a highly potent ACE inhibitor, can also form nanotubes.|
|4000110||MW||Non-competitive inhibitor of angiotensin-1 converting enzyme (ACE), IC₅₀ 9.8 μM.|
|4006116||PR||PR inhibited angiotensin-1 converting enzyme (ACE), IC₅₀ 4.1 μM.|
|4001974||PF||Substrate for human kidney prolinase (prolyl dipeptidase). ACE2 inhibitor, IC₅₀ 0.15 mM.|
|4002549||YL||A dipeptide from β-lactoglobulin showing ACE-inhibitory activity, IC₅₀ 122.1 μmol.|
|4001995||VF||Val-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.|
|4038134||VPP||Antihypertensive tripeptide originally isolated from fermented milk. VPP inhibited angiotensin I-converting enzyme (ACE) with an IC₅₀ value of 9 µM.|
|4008196||VW||The 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.|
|4001976||VY||Antihypertensive 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.|
|Food Source/Intervention(s)||Trial Phase||Trial Phase Sponsor|
|Hemp seed protein and hemp seed protein hydrolysate derived bioactive peptides, hemp seed protein, casein protein||Not applicable||University of Manitoba, Richardson Centre for functional Foods and Nutraceuticals|
|Flaxseed||Phase 2||St. Boniface General Hospital Research Centre; Canadian Institutes of Health Research|
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