Disintegrins

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Structural model of a heterodimer of echistatin

Disintegrins are polypeptides that were first isolated from the venom of various vipers (Viperidae). The sequence is also found as a disintegrin domain in a number of human enzymes, the ADAM metalloproteases . To date, over 25 different disintegrins have been isolated from snake venom.

construction

Disintegrins are water-soluble, cysteine - rich, non- enzymatic peptides that consist of 41 to 84 amino acids in snake venom . In the ADAM proteases, the sequence of the disintegrin domain usually consists of around 90 amino acids. Almost all disintegrins and disintegrin domains, such as also ADAM15 that contain the RGD sequence (Arg-Gly-Asp), for example, to α v β 3 - integrin binds. Other ADAM disintegrins can bind to other integrins. ADAM28 binds to α 4 β 1

In snake venom, the disintegrins cause reduced blood coagulation through binding to the fibrinogen binding receptor - the integrin α IIb β 3 - of the platelets .

The RGD sequence, or as in the case of Obtustatin, the KTS sequence, is presented to the respective receptor at the end of a loop structure of the peptide.

application

The highly specific binding to different receptors make the disintegrins potential active ingredients for the treatment of a number of diseases. The anticoagulant effect can be used, for example, to prevent thrombi . Disintegrins are being tested worldwide for the treatment of cancer , asthma and osteopenia .

The high affinity for certain integrins, which are important for the formation of new blood vessels ( angiogenesis ) during tumor growth (for example α v β 3 ), is of particular interest.

Examples

Selection of some snake disintegrins.

Surname n amino acids n cysteine species
Albolabrin 73 12 White-lipped pit viper ( Trimeresurus albolabris )
Rhodostomine 68 12 Malay moccasin viper ( Calloselasma rhodostoma )
Trigramine 72 12 Green pit viper ( Trimeresurus gramineus )
Batroxostatin 71 12 Common Lance Viper ( Bothrops atrox )
Elegant 73 12 Trimeresurus elegans
Applagin 71 12 Water moccasin otter ( Agkistrodon piscivorus )
Barbourin 73 12 Little Rattlesnake ( Sistrurus m. Barbouri )
Bitistatin 83 14th Puff adder ( Bitis arietans )
Obtustatin 41 8th Levant Otter ( Macroektivena lebetina )
Echistatin 49 8th Common sand otter ( Echis carinatus )
Eristostatin 49 8th MacMahon viper ( Eristicophis macmahoni )
Halysin 71 12 Halysotter ( Gloydius halys )
Kistrin 68 12 Malay moccasin viper ( Calloselasma rhodostoma )
Mambin 59 8th Jameson's Mamba ( Dendroaspis jamesoni )
Tergeminin 73 12 Western Massassauga ( Sistrurus catenatus tergeminus )
Triflavine 70 12 Habu snake ( Trimeresurus flavoviridis )

Individual evidence

  1. ^ DF Seals and SA Courtneidge: The ADAMs family of metalloproteases: multidomain proteins with multiple functions. In: Genes Dev 17, 2003, pp. 7-30. PMID 12514095 (Review)
  2. ↑ LC Bridges et al: The lymphocyte metalloprotease MDC-L (ADAM 28) is a ligand for the integrin α 4 β 1 . In: J Biol Chem 277, 2002, pp. 3784-3792. PMID 11724793
  3. ↑ a b C. P. Chang et al .: Positional importance of Pro53 adjacent to the Arg49-Gly50-Asp51 sequence of rhodostomin in binding to integrin alphaIIbbeta3. In: Biochem J 357, 2001, pp. 57-64. PMID 11415436 , PMC 1221928 (free full text)
  4. ↑ a b L. C. Knight and JE Romano: Functional expression of bitistatin, a disintegrin with potential use in molecular imaging of thromboembolic disease. In: Protein Expr Purif 39, 2005, pp. 307-319. PMID 15642483
  5. ↑ K. Stocker: Use of snake venom proteins in medicine. (PDF; 182 kB) In: Schweiz Med Wochenschr 129, 1999, pp. 205–216.
  6. ^ MA McLane et al: Disintegrins in health and disease. In: Front Biosci 13, 2008, pp. 6617-6637. PMID 18508683 (Review)
  7. ^ S. Swenson et al: Anti-angiogenesis and RGD-containing snake venom disintegrins. In: Curr Pharm Des 13, 2007, pp. 2860-2871. PMID 17979731 (Review)
  8. ↑ a b J. J. Calvette et al .: Identification of the disulfide bond pattern in albolabrin, an RGD-containing peptide from the venom of Trimeresurus albolabris: significance for the expression of platelet aggregation inhibitory activity. In: Biochemistry 30, 1991, pp. 5225-5229. PMID 2036389
  9. ↑ TF Huang et al.: Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. In: J Biol Chem 262, 1987, pp. 16157-16163. PMID 3680247
  10. ↑ B. Rucinski et al .: Batroxostatin, an Arg-Gly-Asp-containing peptide from Bothrops atrox, is a potent inhibitor of platelet aggregation and cell interaction with fibronectin. In: Biochim Biophys Acta 1054, 1990, pp. 257-262. PMID 2207176
  11. ↑ J. Williams et al.: Elegantin and albolabrin purified peptides from viper venoms: homologies with the RGDS domain of fibrinogen and von Willebrand factor. In: Biochim Biophys Acta 1039, 1990, pp. 81-89. PMID 2191722
  12. ↑ A. Scaloni et al: Amino acid sequence and molecular modeling of glycoprotein IIb-IIIa and fibronectin receptor iso-antagonists from Trimeresurus elegans venom. In: Biochem J 319, 1996, pp. 775-782. PMID 8920980
  13. ↑ H. Minoux et al .: Structural analysis of the KGD sequence loop of barbourin, an alphaIIbbeta3-specific disintegrin. In; J Comput Aided Mol Des 14, 2000, pp. 317-327. PMID 10815769
  14. ↑ a b R. M. Scarborough et al.: Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. In: J Biol Chem 266, 1991, pp. 9359-9362. PMID 2033037
  15. ↑ JJ Calvetea et al .: The disulphide bond pattern of bitistatin, a disintegrin isolated from the venom of the viper Bitis arietans. In: FEBS Letters 416, 1997, pp. 197-202. PMID 9369214
  16. ↑ a b c C. Marcinkiewicz et al: Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. In: Cancer Res 63, 2003, pp. 2020-2023. PMID 12727812
  17. ↑ ZR Gan et al.: Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. In: J Biol Chem 263, 1988, pp. 19827-19832. PMID 3198653
  18. ↑ J. Tian et al.: Inhibition of melanoma cell motility by the snake venom disintegrin eristostatin. In: Toxicon 49, 2007, pp. 899-908. PMID 17316731
  19. ↑ a b c L. C. Knight et al: Comparison of iodine-123-disintegrins for imaging thrombi and emboli in a canine model. In: J Nucl Med 37, 1996, pp. 476-482. PMID 8772651
  20. ↑ TF Huang et al: Halysin, an antiplatelet Arg-Gly-Asp-containing snake venom peptide, as fibrinogen receptor antagonist. In: Biochem Pharmacol 42, 1991, pp. 1209-1219. PMID 1888330
  21. ↑ T. Yasuda et al: Kistrin, a polypeptide platelet GPIIb / IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation. In: Circulation 83, 1991, pp. 1038-1047. PMID 1900221
  22. ↑ RS McDowell et al .: Mambin, a potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor structurally related to the short neurotoxins. In: Biochemistry 31, 1992, pp. 4766-4772. PMID 1591238
  23. ↑ TF Huang et al .: A potent antiplatelet peptide, triflavin, from Trimeresurus flavoviridis snake venom. In: Biochem J 277, 1991, pp. 351v357. PMID 1859363

literature

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