1. γ-[Glu](n=1,2)-Phe/-Met/-Val stimulates gastrointestinal hormone (CCK and GLP-1) secretion by activating the calcium-sensing receptor
Juan Yang, Weidong Bai, Xiaofang Zeng, Chun Cui Food Funct. 2019 Jul 17;10(7):4071-4080. doi: 10.1039/c9fo00313d.
This study was conducted to discover the effectiveness of dietary peptides (γ-[Glu](n=1,2)-Phe/-Met/-Val) as stimulators of cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) secretion. The kokumi-active γ-[Glu](n=1,2)-Phe/-Met/-Val at concentrations of 2.5-10 mM would trigger the release of CCK and GLP-1 by activating the calcium-sensing receptor (CaSR). The CaSR-mediated Ca2+/CaM/CaMK pathway was proposed in γ-[Glu](n=1,2)-Phe/-Met/-Val-induced CCK and GLP-1 secretion based on the following results: the exposure to γ-Glu-Phe increased the protein expression level (western blot analysis), the intracellular calcium ([Ca2+]i) mobilization in response to γ-[Glu](n=1,2)-Phe/-Met/-Val was strongly enhanced, and the inhibitors of signaling pathway proteins (NPS-2143, BAPTA-AM, and KN62) abolished partially γ-[Glu](n=1,2)-Phe/-Met/-Val-induced CCK and GLP-1 secretion.
2. Ala-Val-Phe and Val-Phe: ACE inhibitory peptides derived from insect protein with antihypertensive activity in spontaneously hypertensive rats
Lieselot Vercruysse, John Van Camp, Nicole Morel, Pierre Rougé, Griet Herregods, Guy Smagghe Peptides. 2010 Mar;31(3):482-8. doi: 10.1016/j.peptides.2009.05.029. Epub 2009 Jun 12.
In this study, we evaluated the stability/bioavailability and in vivo antihypertensive activity of the tripeptide, Ala-Val-Phe, that was recently purified from insect protein (Spodoptera littoralis; Lepidoptera) and that showed in vitro angiotensin converting enzyme (ACE) inhibitory activity. This tripeptide is partly hydrolyzed by mucosal peptidases to Val-Phe, a more potent in vitro ACE inhibitor. In organ bath experiments using rat aorta, Val-Phe showed ACE inhibition, while Ala-Val-Phe did not. Single oral administration (5mg/kg body weight) to spontaneously hypertensive rats led to a significant decrease in blood pressure for both peptides. Docking experiments indicated an active character for Val-Phe and an inactive character for Ala-Val-Phe as potential inhibitors of human ACE. From our results, it can be suggested that after oral administration of Ala-Val-Phe, Val-Phe is released by in vivo peptidases and is responsible for in vivo activity of Ala-Val-Phe. To the best of our knowledge this is the first report of in vivo antihypertensive activity of peptides derived from insect protein.
3. Design, structure-activity, and molecular modeling studies of potent renin inhibitory peptides having N-terminal Nin-For-Trp (Ftr): angiotensinogen congeners modified by P1-P1' Phe-Phe, Sta, Leu psi[CH(OH)CH2]Val or leu psi[CH2NH]Val substitutions
T K Sawyer, D T Pals, B Mao, D J Staples, A E de Vaux, L L Maggiora, J A Affholter, W Kati, D Duchamp, J B Hester J Med Chem. 1988 Jan;31(1):18-30. doi: 10.1021/jm00396a006.
A structure-conformation-activity investigation of several angiotensinogen (ANG) based inhibitors of human renin modified by either Phe-Phe, Sta, Leu psi[CH2NH]Val, or Leu psi[CH(OH)CH2]Val at the P1-P1' clevage site and P5 Trp(Nin-For) (Ftr) was performed. Specifically, Ac-Ftr-Pro-Phe-His-Phe-Phe-Val-Ftr-NH2 (1) provided a potent (KI = 2.7 X 10(-8) M) P1-P1' Phe-Phe substituted renin inhibitor to initiate these studies. Substitution of the P1-P1' Phe-Phe in compound 1 by Sta effected a 1,000-fold increase in biological potency for the resultant octapeptide Ac-Ftr-Pro-Phe-His-Sta-Val-Ftr-NH2 (10; KI = 6.7 X 10(-11) M). Kinetic analysis of compound 10 showed it to be a competitive inhibitor of human renin catalyzed proteolysis of human ANG. Chemical modifications of the compounds 1 and 10 were evaluated on the basis of comparative human plasma renin inhibitory activities (IC50 values) in vitro. Carboxy-terminal truncation studies on compound 10 showed that the P2' Val and P3' Ftr residues could both be eliminated without significant loss (ca. 10-fold) in renin inhibitory activity as exemplified by the pentapeptide Ac-Ftr-Pro-Phe-His-Sta-NH2 (12; IC50 = 3.8 X 10(-9) M). In addition, the corresponding P1-P1' Leu psi[CH(OH)CH2]Val and Leu psi[CH2NH]Val derivatives of compound 12 were potent renin inhibitors: Ac-Ftr-Pro-Phe-His-Leu psi[CH(OH)CH2]Val-NH2 (13; IC50 = 3.1 X 10(-10) M) and Ac-Ftr-Pro-Phe-His-Leu psi[CH2NH]Val-NH2 (14; IC50 = 2.1 X 10(-8) M). The structure-conformation-activity properties of the N-terminal Ftr substitution of these human renin inhibitors was examined by (1) comparative analysis of several analogues of 1 and Ac-Ftr-Pro-Phe-His-Sta-Ile-NH2 (17; IC50 = 1.0 X 10(-10) M) having P5 site modifications by Trp, His, D-Ftr, and D-His, (2) deletion of the N-terminal Ftr residue from compounds 12 and 17, to provide Ac-Pro-Phe-His-Sta-Ile-NH2 (16; IC50 = 3.1 X 10(-8) M) and Ac-Pro-Phe-His-Sta-NH2 (15; IC50 = 5.6 X 10(-6) M), and (3) computer modeling and dynamics studies of compounds 1 and 17 bound to CKH-RENIN, a simulated human renin model, which were focused on identifying potential intermolecular interactions of their common P5-P2 sequence, Ac-Ftr-Pro-Phe-His, at the enzyme active site.(ABSTRACT TRUNCATED AT 400 WORDS)
