Pharmacological and structural characterization of long-sarafotoxins, a new family of endothelin-like peptides: Role of the C-terminus extension

Mourier, Gilles; Hajj, Mariana; Cordier, Florence; Zorba, Adelajda; Gao, Xing-Huang; Coşkun, Tolga; Herbet, Amaury; Marcon, Elodie; Beau, Fabrice; Delepierre, Muriel; Ducancel, Frédéric; Servent, Denis

doi:10.1016/j.biochi.2011.08.014

Cited by 20 publications

(23 citation statements)

References 30 publications

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“…Sarafotoxin-b was purchased from Sigma (St Quentin Fallavier, France). Sarafotoxin-m and Sarafotoxin-m−Cter were synthesized using an automated chain assembly with a standard Applied Biosystems 433 peptide synthesizer, as previously described [ 6 , 9 ]. Sarafotoxins were synthesized on a Fmoc-Trp(Boc)-wang resin using standard solid phase synthesis techniques.…”

Section: Methodsmentioning

confidence: 99%

“…They interact with endothelin receptors (ET-A and ET-B) situated on the membrane of various cells [ 4 , 5 ]. SRTX-b shows a high sequence homology with endothelin-1 as well as a similar three-dimensional structure [ 6 ]. Long SRTXs, including SRTX-m, were discovered in the venom of Atractaspis microlepidota microlepidota [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…SRTX-m has a longer C-terminus extension with three additional residues “D-E-P”. Solution structures of SRTX-b and-m have revealed well-defined and conserved C1-C15 domains [ 6 ]. All these endothelin-like peptides share the same 3D structure with an extended structure of the four N-terminal amino acids, a bend between positions +5 and +8, and an alpha-helical conformation of the segment Lys9-Cys-15 [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Surprisingly, and despite these differences, the in vivo toxicity of SRTX-m in the mouse is very similar to that of SRTX-b [ 7 ]. It has been hypothesised that endogenous maturation by specific endoproteases of the prey, may remove the longer C-terminus extension of SRTX-m, resulting in a toxic effect similar to SRTX-b [ 6 ]. To assess this hypothesis, in this study we investigated the in vivo cardiovascular effects of SRTX-b, SRTX-m and SRTX-m−Cter, a C-terminus truncated form of SRTX-m.…”

Section: Introductionmentioning

confidence: 99%

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Short- versus Long-Sarafotoxins: Two Structurally Related Snake Toxins with Very Different in vivo Haemodynamic Effects

et al. 2015

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Sarafotoxin-m (24 amino acids) from the venom of Atractaspis microlepidota microlepidota was the first long-sarafotoxin to be identified, while sarafotoxin-b (21 aa) is a short-sarafotoxin from Atractaspis engaddensis. Despite the presence of three additional C-terminus residues in sarafotoxin-m, these two peptides display a high sequence homology and share similar three-dimensional structures. However, unlike sarafotoxin-b, sarafotoxin-m shows a very low in vitro affinity for endothelin receptors, but still has a very high in vivo toxicity in mammals, similar to that of sarafotoxin-b. We have previously demonstrated, in vitro, the crucial role of the C-terminus extension in terms of pharmacological profiles and receptor affinities of long- versus short-sarafotoxins. One possible hypothesis to explain the high in vivo toxicity of sarafotoxin-m could be that its C-terminus extension is processed in vivo, resulting in short-like sarafotoxin. To address this possibility, we investigated, in the present study, the in vivo cardiovascular effects of sarafotoxin-b, sarafotoxin-m and sarafotoxin-m−Cter (sarafotoxin-m without the C -terminus extension). Male Wistar rats were anaesthetised and mechanically ventilated. Invasive haemodynamic measurements and echocardiographic measurements of left and right ventricular function were performed. The rats were divided into four groups that respectively received intravenous injections of: saline, sarafotoxin-b (one LD50), sarafotoxin-m (one LD50) or sarafotoxin-m−Cter (one LD50). All measurements were performed at baseline, at 1 minute (+1) and at 6 minutes (+6) after injection. Results: Sarafotoxin-b and sarafotoxin-m-Cter decreased cardiac output and impaired left ventricle systolic and diastolic function, whilst sarafotoxin-m decreased cardiac output, increased airway pressures and led to acute right ventricular dilatation associated with a decreased tricuspid annulus peak systolic velocity. Sarafotoxin-b and sarafotoxin-m−Cter appear to exert toxic effects via impairment of left ventricular function, whilst sarafotoxin-m increases airway pressures and impairs right ventricular function. These results do not support the hypothesis of an in vivo processing of long sarafotoxins.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Short- versus Long-Sarafotoxins: Two Structurally Related Snake Toxins with Very Different in vivo Haemodynamic Effects

et al. 2015

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“…The toxin cocktail comprises of molecules that target various key regulatory pathways and a diverse array of protein families has been recruited into the myriad of animal venoms [13,14,15,16]. Atractaspis venoms have been poorly characterized as a whole and most prior studies have focused their attention on sarafotoxins [2,8,9,10,17]. Nonetheless, based on the phylogenetic placement of Atractaspis , as well as current knowledge of various snake venoms, we might expect a wide range of toxins or venom compounds to be secreted in their venom gland lumen.…”

Section: Introductionmentioning

confidence: 99%

Atractaspis aterrima Toxins: The First Insight into the Molecular Evolution of Venom in Side-Stabbers

Terrat

Sunagar

Fry

et al. 2013

Toxins

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Although snake venoms have been the subject of intense research, primarily because of their tremendous potential as a bioresource for design and development of therapeutic compounds, some specific groups of snakes, such as the genus Atractaspis, have been completely neglected. To date only limited number of toxins, such as sarafotoxins have been well characterized from this lineage. In order to investigate the molecular diversity of venom from Atractaspis aterrima—the slender burrowing asp, we utilized a high-throughput transcriptomic approach completed with an original bioinformatics analysis pipeline. Surprisingly, we found that Sarafotoxins do not constitute the major ingredient of the transcriptomic cocktail; rather a large number of previously well-characterized snake venom-components were identified. Notably, we recovered a large diversity of three-finger toxins (3FTxs), which were found to have evolved under the significant influence of positive selection. From the normalized and non-normalized transcriptome libraries, we were able to evaluate the relative abundance of the different toxin groups, uncover rare transcripts, and gain new insight into the transcriptomic machinery. In addition to previously characterized toxin families, we were able to detect numerous highly-transcribed compounds that possess all the key features of venom-components and may constitute new classes of toxins.

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QuanPol: A full spectrum and seamless QM/MM program

Thellamurege

Cui

et al. 2013

J. Comput. Chem.

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The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree-Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self-consistent field method, Møller-Plesset perturbation theory method, and time-dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self-consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented.

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Pharmacological and structural characterization of long-sarafotoxins, a new family of endothelin-like peptides: Role of the C-terminus extension

Cited by 20 publications

References 30 publications

Short- versus Long-Sarafotoxins: Two Structurally Related Snake Toxins with Very Different in vivo Haemodynamic Effects

Short- versus Long-Sarafotoxins: Two Structurally Related Snake Toxins with Very Different in vivo Haemodynamic Effects

Atractaspis aterrima Toxins: The First Insight into the Molecular Evolution of Venom in Side-Stabbers

QuanPol: A full spectrum and seamless QM/MM program

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