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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Available from: Goran Neshich, Oct 05, 2015
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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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    ABSTRACT: A bradykinin-potentiating peptide (BPP) from Amazon Bothrops atrox venom with m/z 1384.7386 was identified and characterized by collision induced dissociation (CID) using an ESI-MS/MS spectra obtained in positive ion mode on a hybrid Qq-oaTOF mass spectrometer, Xevo G2 QTof MS (Waters, Manchester, UK). De novo peptide sequence analysis of the CID fragmentation spectra showed the amino acid sequence ZKWPRPGPEIPP, with a pyroglutamic acid and theoretical monoisotopic m/z 1384.7378, which is similar to experimental data, showing a mass accuracy of 0.6 ppm. The peptide is homologous to other BPP from Bothrops moojeni and was named as BPP-BAX12.
    Toxins 02/2013; 5(2):327-35. DOI:10.3390/toxins5020327 · 2.94 Impact Factor
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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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    ABSTRACT: Chagas' disease, caused by Trypanosoma cruzi, affects 16-18 million people in Central and South America. Patient treatment is based on drugs that have toxic effects and limited efficacy. Therefore, new chemotherapeutic agents need to be developed. Snake venoms are sources of natural compounds used in various medical treatments. We observed that Crotalus viridis viridis venom was effective against all developmental forms of T. cruzi. Ultrastructural analysis revealed swelling of mitochondria, blebbing and disruption of the plasma membrane, loss of cytoplasm components and morphological changes of the cell. Staining with propidium iodide and rhodamine 123 confirmed the observed alterations in the plasma and mitochondrial membranes, respectively. The effects of the venom on the parasite intracellular cycle were also analysed. Pre-infected LLC-MK2 cells incubated with Cvv venom showed a 76-93% reduction in the number of parasites per infected cell and a 94-97.4% reduction in the number of parasites per 100 cells after 96 h of infection. Free trypomastigotes harvested from the supernatants of Cvv venom-treated cells were incapable of initiating a new infection cycle. Our data demonstrate that Cvv venom can access the host cell cytoplasm at concentrations that cause toxicity only to the amastigote forms of T. cruzi, and yields altered parasites with limited infective capacity, suggesting the potential use of Cvv venom in Chagas' disease chemotherapy.
    Parasitology 01/2011; 138(1):46-58. DOI:10.1017/S0031182010000958 · 2.56 Impact Factor
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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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    ABSTRACT: Venoms comprise mixtures of peptides and proteins tailored by Natural Selection to act on vital systems of the prey or victim. Here we review our proteomic protocols for uncoiling the composition, immunological profile, and evolution of snake venoms. Our long-term goal is to gain a deep insight of all viperid venom proteomes. Knowledge of the inter- and intraspecies ontogenetic, individual, and geographic venom variability has applied importance for the design of immunization protocols aimed at producing more effective polyspecific antivenoms. A practical consequence of assessing the cross-reactivity of heterologous antivenoms is the possibility of circumventing the restricted availability of species-specific antivenoms in some regions. Further, the high degree of target specificity makes toxins valuable scaffolds for drug development.
    FEBS letters 04/2009; 583(11):1736-43. DOI:10.1016/j.febslet.2009.03.029 · 3.17 Impact Factor
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