The modular nature of bradykinin-potentiating peptides isolated from snake venoms

Abstract

Bradykinin-potentiating peptides (BPPs) are molecules discovered by Sergio Ferreira – who found them in the venom of Bothrops jararaca in the 1960s – that literally potentiate the action of bradykinin in vivo by, allegedly, inhibiting the angiotensin-converting enzymes. After administration, the global physiological effect of BPP is the decrease of the blood pressure. Due to this interesting effect, one of these peptides was used by David Cushman and Miguel Ondetti to develop a hypotensive drug, the widely known captopril, vastly employed on hypertension treatment. From that time on, many studies on BPPs have been conducted, basically describing new peptides and assaying their pharmacological effects, mostly in comparison to captopryl. After compiling most of these data, we are proposing that snake BPPs are ‘modular’ peptidic molecules, in which the combination of given amino acid ‘blocks’ results in the different existing peptides (BPPs), commonly found in snake venom. We have observed that there would be mandatory modules (present in all snake BPPs), such as the N-terminal pyroglutamic acid and C-terminal QIPP, and optional modules (amino acid blocks present in some of them), such as AP or WAQ. Scattered between these modules, there might be other amino acids that would ‘complete’ the peptide, without disrupting the signature of the classical BPP. This modular arrangement would represent an important evolutionary advantage in terms of biological diversity that might have its origins either at the genomic or at the post-translational modification levels. Regardless of the modules’ origin, the increase in the diversity of peptides has definitely been essential for snakes’ success on nature.

Organic and Peptidyl Constituents of Snake Venoms: The Picture Is Vastly More Complex Than We Imagined

“…This tripeptide was abundant in all pitviper venoms that we surveyed, and it even occurred at modest concentrations in C. cerastes , B. multicinctus , and D. polylepis venoms ( Figure 18 ). Sciani and Pimenta [ 263 ] reported that this tripeptide is found as a module in 9% of all bradykinin-potentiating peptides. Munekiyo and Mackessy [ 264 ] found it in ten rattlesnake venoms, and reported that it inhibits and stabilizes several of the major metalloproteases in these venoms.…”

“…With its C-terminal Pro–Arg sequence, pEPR resembles a shortened version of oligopeptides with 5 or 11 residues. Pyroglutamyl tripeptides may represent hypotensive peptides with only two modules, following the proposal of Sciani and Pimenta [ 263 ].…”

Evaluation of KIM-1 as an early biomarker of snakebite-induced AKI in mice

“…In contrast, serum creatinine levels were increased to 1.18 mg/dL while the basal creatine levels were 0.4 mg/dL, suggesting severe injury. Bothrops venom causes decrease in the blood pressure (Sciani and Pimenta, 2017) and functional injuries such as vasospasm might be existed on the kidney. Also, BinsV might induce muscle injures as the other toxins (White, 2000) and this could increase serum creatinine, which are unspecific marker (Debelmas et al, 2018).…”

LmrBPP9: A synthetic bradykinin-potentiating peptide from Lachesis muta rhombeata venom that inhibits the angiotensin-converting enzyme activity in vitro and reduces the blood pressure of hypertensive rats

“…Most BPPs found in snake venoms display a general structure pattern that is represented by < E-X n -P-X n -P-X n -I-P-P, with < E being a pyroglutamic acid and X any amino acid, but Cysteine [11]. According to previous studies [25] that report the cDNA library of the venom gland of L. muta, the sequences of BPPs in this species' venom display great similarity among each other, which may explain the similar retention time for some components.…”

“…BPPs were originally described in the venom of Bothrops jararaca as proline-rich oligopeptides, containing 5-13 amino acid residues [10]. Structurally, many of them display a pyroglutamic acid at the N-terminal and a characteristic C-terminus sequence ending on IPP [11], which is essential for binding of the peptide on ACE catalytic site [12,13].…”