Using bradykinin-potentiating peptide structures to develop new antihypertensive drugs

Center of Applied Toxinology, Instituto Butantan, São Paulo, SP, Brazil
Genetics and molecular research: GMR (Impact Factor: 0.78). 02/2004; 3(4):554-63.
Source: PubMed


Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2', S1' and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selective ACE inhibitors with high stability and improved pharmacological profiles.

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    • "Snake venoms have been recognized as an extensible source of bioactive peptides with potential biotechnological applications in medicine [1]. Due to their high degree of target specificity, venom toxins have been increasingly used as lead compounds in the development of drug prototypes [2]. One of the most successful examples has been Captopril®, an antihypertensive drug based on a bradykinin-potentiating peptide (BPP) isolated from Brazilian Bothropoides (Bothrops) jararaca venom [3,4]. "
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    • "One of these drugs, Captopril, is the first commercial inhibitor of angiotensin I-converting enzyme (ACE) and is used for the treatment of human hypertension. This compound was developed from studies of Bothrops jararaca venom and its bradykinin-potentiating peptides (BPPs) (Fernandez et al. 2004). Snake venom proteins have been used to kill HIV (Zhang et al. 2003), the protozoan parasites Plasmodium falciparum (Zieler et al. 2001) and Leishmania spp. "
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    • "The medical uses of scorpion and snake venoms are well documented in folk remedies, and in Western and Chinese traditional medicine [4] [5]. However, extensive investigations on venom compounds as natural leads for the generation of pharmaceutical products have only been performed in the last decades, after a bradykinin-potentiating peptide isolated from the venom of the Brazilian viper Bothrops jararaca was developed in the 1950s into the first commercial angiotensin I-converting enzyme (ACE)-inhibiting drug, captopril Ò , for the treatment of renovascular hypertension [6] [7]. The latest example of development of a toxin into an approved drug by the US Food and Drug Administration (FDA) (December 2004) is ziconotide (Prialt Ò ), a synthetic non-opioid, non-NSAID, non-local anesthetic drug originating from the cone snail Conus magus peptide x-conotoxin M-VII-A, an N-type calcium channel blocker. "
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