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Kallech-Ziri O.,Institute Pasteur Of Tunis | Luis J.,Aix - Marseille University | Faljoun Z.,ERT 62 | Sabatier J.-M.,ERT 62 | And 5 more authors.
Letters in Drug Design and Discovery | Year: 2010

Disintegrins are natural toxins found in snake venom having anti angiogenic activity. The KTS disintegrins group appears to be the most interesting as specific blocking agent of tumor growth. We report the chemical synthesis of three KTS disintegrins (Lebestatin, Obtustatin and Viperistatin) carried out with different substitution. The activity of these synthetic peptides (41 aa) and native Lebestatin purified from venom was compared with cell adhesion and migration assays. Synthetic and native Lebestatin inhibit cell adhesion of PC12 cells at 0.2 nM and integrin-dependent migration of CHO cells at 1 nM. This study shows that Lebestatin has the highest activity followed by Obtustatin and then Viperistatin in the two assays. Circular dichroism spectra of these KTS disintegrins show that their folding is similar. Molecular modeling shows that two arginines (8 and 24) and two lysines (21 and 32) have probably their chemical function interacting with integrins in protruding from the surface of Lebestatin. This study should help to design a lead compound to discover a new family of anti-angiogenic drugs. © 2010 Bentham Science Publishers Ltd.


Fajloun Z.,ERT 62 | Fajloun Z.,Lebanese University | Andreotti N.,ERT 62 | Fathallah M.,French Institute of Health and Medical Research | And 2 more authors.
Journal of Peptide Science | Year: 2011

Maurotoxin (MTX) is a 34-residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the α-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic α/β scaffold of scorpion toxins. MTXPi1 is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Here, using MTX and/or MTXPi1 as models, we investigated how the type of folding influences toxin recognition of the Shaker B potassium channel. Amino acid residues of MTX that were studied for Shaker B recognition were selected on the basis of their homologous position in charybdotoxin, a three disulfide-bridged scorpion toxin also active on this channel type. These residues favored either an MTX- or MTXPi1-like folding. Our data indicate clearly that Lys23 and Tyr32 (two out of ten amino acid residues studied) are the most important residues for Shaker B channel blockage by MTX. For activity on SKCa channels, the same amino acid residues also affect, directly or indirectly, the recognition of SK channels. The molecular modeling technique and computed docking indicate the existence of a correlation between the half cystine pairings of the mutated analogs and their activity on the Shaker B K+ channel. Overall, mutations in MTX could, or could not, change the reorganization of disulfide bridges of this molecule without affecting its α/β scaffold. However, changing of the peptide backbone (cross linking disulfide bridges from MTX-like type vs MTXPi1-like type) appears to have less impact on the molecule activity than mutation of certain key amino acids such as Lys23 and Tyr32 in this toxin. Maurotoxin (MTX) is a 34-residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the α-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic α/β scaffold of scorpion toxins. MTXPi1 is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.


PubMed | ERT 62
Type: Journal Article | Journal: Journal of peptide science : an official publication of the European Peptide Society | Year: 2011

Maurotoxin (MTX) is a 34-residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the -KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C(1) C(5) , C(2) C(6) , C(3) C(4) , and C(7) C(8) (instead of the conventional C(1) C(5) , C(2) C(6) , C(3) C(7) , and C(4) C(8) , herein referred to as Pi1-like) that does not prevent its folding along the classic / scaffold of scorpion toxins. MTX(Pi1) is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Here, using MTX and/or MTX(Pi1) as models, we investigated how the type of folding influences toxin recognition of the Shaker B potassium channel. Amino acid residues of MTX that were studied for Shaker B recognition were selected on the basis of their homologous position in charybdotoxin, a three disulfide-bridged scorpion toxin also active on this channel type. These residues favored either an MTX- or MTX(Pi1) -like folding. Our data indicate clearly that Lys(23) and Tyr(32) (two out of ten amino acid residues studied) are the most important residues for Shaker B channel blockage by MTX. For activity on SKCa channels, the same amino acid residues also affect, directly or indirectly, the recognition of SK channels. The molecular modeling technique and computed docking indicate the existence of a correlation between the half cystine pairings of the mutated analogs and their activity on the Shaker B K(+) channel. Overall, mutations in MTX could, or could not, change the reorganization of disulfide bridges of this molecule without affecting its / scaffold. However, changing of the peptide backbone (cross linking disulfide bridges from MTX-like type vs MTX(Pi1) -like type) appears to have less impact on the molecule activity than mutation of certain key amino acids such as Lys(23) and Tyr(32) in this toxin.

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