Bradykinin-derived peptides

ACE inhibitor drugs were developed by modelling interaction with the active site of the enzyme of a snake-venom-derived bradykinin-potentiating peptide, and from this the necessary structure of non-peptide inhibitors was inferred. The first such ACE inhibitor used medicinally was caplopril. Later examples in clinical use include cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril. Several ACE inhibitors are now administered clinically as prodrugs - which have good bioavailability, but are inactive in their own right. They are then converted to the active molecule in vivo, usually by esterases (e.g. enalapril to enalaprilat. and ramipril to ramiprilat). 

Thi ,DPhe BK [Thi ,DPhe ]-bradykinin. bradykinin-potentiating peptide teprotide. bradykinin potentiator B teprotide. BRADYKININ RECEPTOR AGONISTS act at sites recognizing members and derivatives of the bradykinin family of hormone peptides - kinins - of which bradykinin (BK) and kallidin (lysyl-bradykinin Lys-BK KD) are the main mammalian members. The bradykinin family is distinct from the tachykinin family of peptides, though both have profound hypotensive actions and contract many intestinal and other smooth muscles. Historically, it was noted that the former action was relatively slow-developing, hence the name bradykinin. Notable actions of bradykinin and kallidin are to dilate blood vessels and increase their permeability to plasma proteins, and to stimulate sensory nerve C-fibres. These actions are pro-inflammatory, and reflect the fact that the kinin-formation system is activated in inflammation, and enzymes (kallikreins) form the kinins from blood-borne or tissue precursors (kininogens) on injurious insult. 

Fujita, H., Usui, H., Kurahashi, K., and Yoshikawa, M. 1995. Isolation and characterization of ovokinin, a Bradykinin Bi agonist peptide derived from ovalbumin. Peptides 46, 780-790. 

FR 173657 is a non-peptide quinolinyl derivative (Bz-subtype) BRADYKININ RECEPTOR ANTAGONIST. It did not advance to clinical development, but has been used as a pharmacological tool. 

Figure 16.19 Comparison of the experimental (s3nnbols) overloaded elution band profiles of a mixture of the closely related peptides bradykinin and kallidin on a Zorbax SB-C18150 x 0.5 mm column eluted with ACN/H2O, 20/80 v/v (+ 0.5% TFA), for a loading factor Ly = 0.29% and the profiles calculated with the ED (solid lines) and the FOR models (dashed lines), (a) Parameters of the FOR model derived from conventional correlations, (b) Dm in the FOR model optimized numerically at 1 x 10 cm /s. Reproduced with permission from D. Zhou, X. Liu, K. Kaczmarski, A. Felinger, G. Guiochon, Biotech. Prog. 19 (2003) 945 (Figure 4.) 2003, American Chemical Society.

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

The peptide bradyldnin and its derivatives have been very useful in elucidating the specificity of prolyl hydroxylase (131). The primary sequence of bradykinin is H-Arg-Pro-Pro-Gly-Phe Ser-Pro-Phe ... 

The intensive studies on the genetic code and on the proteins in recent years have led to a fairly good understanding of the mechanism of protein biosynthesis . The biosynthetic mechanism involved in the formation of peptides has not yet been studied in equal detail. Some physiologically active peptides like bradykinin and angiotensin are known to be derived from proteins by a specific enzymatic hydrolysis. Other peptides, like glutathione - , ophthalmic acid , the nucleotide-pentapeptide from Staph, aureus and y-polyglutamic acid have been shown to require for their synthesis only a soluble enzyme system. Their biosynthetic mechanism is therefore entirely different from that of the proteins. Such a different type of mechanism has also been demonstrated lately to be involved in the synthesis of peptide antibiotics. 

A vasodilating peptide with smooth-muscle stimulating action was described by Rocha e Silva, Beraldo and Rosenfeld in 1949 and named bradykinin. It is produced by the action of trypsin or snake venoms on plasma. A similar substance, kallidin, was prepared shortly afterwards by Werle and Berek using the protease kalUkrein. Other peptides with similar properties have been described and the general term kinins or, when derived from plasma proteins, plasma kinins has been recommended. The best-known kinin, bradykinin, has recently been shown to be a nonapeptide, and its structure confirmed by synthesis - . When injected subcutaneously into laboratory animals and man, bradykinin causes vasodilatation, increased vascular permeability, leucocyte infiltration and pain. 

A number of factors, including tissue damage, allergic reactions, viral infections, and other inflammatory events, activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation, and increased vascular permeability. Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF). 

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