Bradykinin snake venom

The teprotide BPP9a (bradykinin-potentiating peptide) 76 and analogous BPP peptides170), which have been isolated from snake venom, are taken up by ACE in competition with the substrate angiotensin I with far greater affinity. 

Silva MR, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth-muscle-stimulating factor released from plasma globulin by snake venoms and by trypsin. Am. J. Physiol. 1949 156 261-273. 

Bradykinin and kallidin ate potent vasodilators and hypotensive agents that have different peptide structures bradykinin is a nonapeptide, whereas kallidin is a decapepttde. Kdlidin is ly.syl-bradykinin that is. it has an additional lysine at the NH2 terminus of the chain. Tliese two compounds arc made available from kininogen. a hlood globulin, on hydrolysis. Trypsin, plasmin, or the proteases of certain snake venoms can catalyze the hydrolysis of kininogen. 

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). 

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. 

Since 1948, it has been known that the vasodUatory effect of the snake venom from the Brazilian lancehead snake is connected to bradykinin. Important contributions towards clarifying the mode of action of the toxic principle are due to the research of the Brazilian pharmacologist Sergio Henrique Ferreira. One of... 

While Ferreira continued to focus on bradykinin. Sir John R. Vane (1927-2004) and Yeshwant S. Bakhle recognised that the snake venom also had an effect on the renin-angiotensin system. Miguel Ondetti (1930-2004) and David Cushman (1939-2000) at Squibb (now Bristol-Myers-Squibb) isolated and characterised six other ACE-inhibitory peptides, among them teprotide (IC50 250 nM). [7, 8]... 

The snake venom peptide BPPsa and captopril bind at the active site of ACE in a competitive manner, thereby-replacing angiotensin I and bradykinin. 

M. Rocha e Silva, W.T.Beraldo and G. Rosenfeld, Bradykinin, a Hypotensive and Smooth Muscle Stimulating Factor Released from Plasma Globulin by Snake Venoms and by Trypsin, Am. J. Physiol. 156, 261-273 (1949). 

Later, Rocha e Silva and coworkers in 1949 observed the release of a peptide from inactive substrate in the plasma that was evoked by trypsin and certain snake venoms. The name of this peptide, bradykinin (from the Greek bradys = slow), implies a substance causing slow contraction of smooth muscle. 

Other kininogenases have been isolated from various sources and identified among known enzymes. Trypsin is the most characteristic, and its kinin-ieleasmg potency led to the discovery of bradykinin (see Introduction). Among others, snake venoms Bothrops jararaca, Crotallus adamanteus and many others) and bacterial enzymes Clostridium histolyticum. Bacillus subtilis) should be mentioned. 

Bradykinin is a strong hypotensive agent because of its vasodilating action and is a potent substance for increasing capillary permeability. Snake venoms contain enzymes that release bradykinin from its plasma globulin precursor bradykininogen. 

The bradykinin potentiating effect of a series of peptides present in the venom of the South American poisonous snake Bothrops jararaca has already been mentioned in connection with the inhibition of the angiotensin converting enzyme (cf. p. 183) [33]. These proline rich peptides... 

Constit. of the venom of the snakes Bothrops insularis, Trimeresurus flavoviridis and T. okinavensis. Bradykinin potentiator. 

---