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Echistatin, α1 isoform

* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

Echistatin, α1 isoform is a potent and irreversible αVβ3 integrin antagonist (Ki = 0.27 nM). It exhibits inhibitory activity for bone reabsorption (IC50 = 0.1 nM) and prevents ADP-induced platelet aggregation by inhibiting glycoprotein IIb/IIIa (GpIIb/IIIa, αIIbβ3) receptors (IC50 = 30 nM) in vitro.

Category

Peptide Inhibitors

Catalog number

BAT-010345

CAS number

154303-05-6

Molecular Formula

C217H341N71O74S9

Molecular Weight

5417.05

Specification
Reference Reading

IUPAC Name

(4S)-5-[[(1R,4aS,6R,7aS,9R,12S,12aS,15aR,21S,24S,26aS,27R,29aS,32R,35S,38S,41S,44S,47S,53S,56S,59R,62S,65S,68S,71S,77S,80S,83S,86S,89S,92S,95R,98S)-15a-[(2S)-2-[[(2S)-1-[[(2S)-4-amino-1-[(2S)-2-[[(2S)-1-[[(2S)-6-amino-1-[[2-[(2S)-2-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1,4-dioxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]-4a,35,44,62-tetrakis(4-aminobutyl)-26a,98-bis(2-amino-2-oxoethyl)-38-benzyl-56-[(2S)-butan-2-yl]-29a,65,71-tris(3-carbamimidamidopropyl)-24,47-bis(2-carboxyethyl)-12a,77,80,86,89-pentakis(carboxymethyl)-7a,53-bis[(1R)-1-hydroxyethyl]-21-(hydroxymethyl)-92-[(4-hydroxyphenyl)methyl]-68-methyl-41-(2-methylpropyl)-83-(2-methylsulfanylethyl)-2a,5a,8,8a,10a,11,13a,17,20,23,25a,26,28a,31a,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75,78,81,84,87,90,93,96,99-heptatriacontaoxo-3,4,17a,18a,21a,22a,29,30-octathia-a,3a,6a,7,9a,10,11a,14a,16,19,22,24a,25,27a,30a,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76,79,82,85,88,91,94,97-heptatriacontazapentacyclo[57.50.10.86,32.49,95.012,16]hentriacontahectan-27-yl]amino]-4-amino-5-oxopentanoic acid

Synonyms

H-Glu-Cys(1)-Glu-Ser-Gly-Pro-Cys(2)-Cys(3)-Arg-Asn-Cys(1)-Lys-Phe-Leu-Lys-Glu-Gly-Thr-Ile-Cys(4)-Lys-Arg-Ala-Arg-Gly-Asp-Asp-Met-Asp-Asp-Tyr-Cys(2)-Asn-Gly-Lys-Thr-Cys(3)-Asp-Cys(4)-Pro-Arg-Asn-Pro-His-Lys-Gly-Pro-Ala-Thr-OH; L-alpha-glutamyl-L-cysteinyl-L-alpha-glutamyl-L-seryl-glycyl-L-prolyl-L-cysteinyl-L-cysteinyl-L-arginyl-L-asparagyl-L-cysteinyl-L-lysyl-L-phenylalanyl-L-leucyl-L-lysyl-L-alpha-glutamyl-glycyl-L-threonyl-L-isoleucyl-L-cysteinyl-L-lysyl-L-arginyl-L-alanyl-L-arginyl-glycyl-L-alpha-aspartyl-L-alpha-aspartyl-L-methionyl-L-alpha-aspartyl-L-alpha-aspartyl-L-tyrosyl-L-cysteinyl-L-asparagyl-glycyl-L-lysyl-L-threonyl-L-cysteinyl-L-alpha-aspartyl-L-cysteinyl-L-prolyl-L-arginyl-L-asparagyl-L-prolyl-L-histidyl-L-lysyl-glycyl-L-prolyl-L-alanyl-L-threonine (2->11),(7->32),(8->37),(20->39)-tetrakis(disulfide)

Appearance

White Lyophilized Solid

Purity

>98%

Sequence

ECESGPCCRNCKFLKEGTICKRARGDDMDDYCNGKTCDCPRNPHKGPAT (Disulfide bridge: Cys2 and Cys11, Cys7 and Cys32, Cys8 and Cys37, Cys20 and Cys39)

Storage

Store at -20°C

Solubility

Soluble in Water (1 mg/mL)

InChI

InChI=1S/C217H341N71O74S9/c1-11-102(4)166-208(356)278-143-97-370-371-99-145(212(360)288-71-32-46-148(288)206(354)260-121(43-28-67-239-217(233)234)183(331)271-136(79-152(226)296)211(359)287-70-31-47-149(287)207(355)270-128(76-110-85-235-100-245-110)190(338)251-113(35-15-20-59-218)174(322)243-89-156(300)285-68-29-44-146(285)204(352)247-104(6)171(319)284-169(107(9)292)213(361)362)280-196(344)135(84-165(316)317)269-202(350)144-98-369-366-94-140-199(347)256-120(42-27-66-238-216(231)232)182(330)265-130(78-151(225)295)191(339)275-139(198(346)255-118(39-19-24-63-222)181(329)262-126(74-108-33-13-12-14-34-108)188(336)261-125(73-101(2)3)187(335)253-116(37-17-22-61-220)180(328)257-122(53-56-159(304)305)175(323)241-88-155(299)281-167(105(7)290)210(358)282-166)93-365-364-92-138(273-172(320)112(223)52-55-158(302)303)197(345)258-123(54-57-160(306)307)184(332)272-137(91-289)177(325)244-90-157(301)286-69-30-45-147(286)205(353)277-142(203(351)276-140)96-368-367-95-141(201(349)264-129(77-150(224)294)176(324)242-86-153(297)248-115(36-16-21-60-219)186(334)283-168(106(8)291)209(357)279-144)274-189(337)127(75-109-48-50-111(293)51-49-109)263-194(342)134(83-164(314)315)268-195(343)133(82-163(312)313)266-185(333)124(58-72-363-10)259-193(341)132(81-162(310)311)267-192(340)131(80-161(308)309)249-154(298)87-240-173(321)114(40-25-64-236-214(227)228)250-170(318)103(5)246-178(326)119(41-26-65-237-215(229)230)252-179(327)117(254-200(143)348)38-18-23-62-221/h12-14,33-34,48-51,85,100-107,112-149,166-169,289-293H,11,15-32,35-47,52-84,86-99,218-223H2,1-10H3,(H2,224,294)(H2,225,295)(H2,226,296)(H,235,245)(H,240,321)(H,241,323)(H,242,324)(H,243,322)(H,244,325)(H,246,326)(H,247,352)(H,248,297)(H,249,298)(H,250,318)(H,251,338)(H,252,327)(H,253,335)(H,254,348)(H,255,346)(H,256,347)(H,257,328)(H,258,345)(H,259,341)(H,260,354)(H,261,336)(H,262,329)(H,263,342)(H,264,349)(H,265,330)(H,266,333)(H,267,340)(H,268,343)(H,269,350)(H,270,355)(H,271,331)(H,272,332)(H,273,320)(H,274,337)(H,275,339)(H,276,351)(H,277,353)(H,278,356)(H,279,357)(H,280,344)(H,281,299)(H,282,358)(H,283,334)(H,284,319)(H,302,303)(H,304,305)(H,306,307)(H,308,309)(H,310,311)(H,312,313)(H,314,315)(H,316,317)(H,361,362)(H4,227,228,236)(H4,229,230,237)(H4,231,232,238)(H4,233,234,239)/t102-,103-,104-,105+,106+,107+,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,166-,167-,168-,169-/m0/s1

InChI Key

KZMZKUVIDVBQGX-SSUNCQRMSA-N

Canonical SMILES

CCC(C)C1C(=O)NC2CSSCC(NC(=O)C(NC(=O)C3CSSCC4C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)N5CCCC5C(=O)NC(CSSCC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NC(C(=O)N3)C(C)O)CCCCN)CC(=O)N)NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC2=O)CCCCN)CCCNC(=N)N)C)CCCNC(=N)N)CC(=O)O)CC(=O)O)CCSC)CC(=O)O)CC(=O)O)CC6=CC=C(C=C6)O)C(=O)N4)CO)CCC(=O)O)NC(=O)C(CCC(=O)O)N)C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)N1)C(C)O)CCC(=O)O)CCCCN)CC(C)C)CC7=CC=CC=C7)CCCCN)CC(=O)N)CCCNC(=N)N)CC(=O)O)C(=O)N8CCCC8C(=O)NC(CCCNC(=N)N)C(=O)NC(CC(=O)N)C(=O)N9CCCC9C(=O)NC(CC1=CNC=N1)C(=O)NC(CCCCN)C(=O)NCC(=O)N1CCCC1C(=O)NC(C)C(=O)NC(C(C)O)C(=O)O

1. α5β1 integrin induces the expression of noncartilaginous procollagen gene expression in articular chondrocytes cultured in monolayers

Tetsuo Yamaguchi, Yasuko Ikeda, Takumi Nakagawa, Shigeto Tohma, Nobuho Tanaka, Hiroshi Furukawa, Naoshi Fukui, Hiroyuki Mitomi Arthritis Res Ther . 2013 Sep 19;15(5):R127. doi: 10.1186/ar4307.

Introduction:Articular chondrocytes undergo an obvious phenotypic change when cultured in monolayers. During this change, or dedifferentiation, the expression of type I and type III procollagen is induced where normal chondrocytes express little type I and type III procollagen. In this study, we attempted to determine the mechanism(s) for the induction of such procollagen expression in dedifferentiating chondrocytes.Methods:All experiments were performed using primary-cultured human articular chondrocytes under approval of institutional review boards. Integrin(s) responsible for the induction of type I and type III procollagen expression were specified by RNAi experiments. The signal pathway(s) involved in the induction were determined by specific inhibitors and RNAi experiments. Adenovirus-mediated experiments were performed to identify a small GTPase regulating the activity of integrins in dedifferentiating chondrocytes. The effect of inhibition of integrins on dedifferentiation was investigated by experiments using echistatin, a potent disintegrin. The effect of echistatin was investigated first with monolayer-cultured chondrocytes, and then with pellet-cultured chondrocytes.Results:In dedifferentiating chondrocytes, α5β1 integrin was found to be involved in the induction of type I and type III procollagen expression. The induction was known to be mediated by v-akt murine thymoma viral oncogene homolog (AKT) signaling. Among the three AKT isoforms, AKT1 seemed to be most involved in the signaling. Elated RAS viral (r-ras) oncogene homolog (RRAS) was considered to regulate the progression of dedifferentiation by modulating the affinity and avidity of α5β1 integrin to ligands. Echistatin inhibited dedifferentiation of monolayer-cultured chondrocytes. Furthermore, the matrix formed by pellet-cultured chondrocytes more closely resembled that of normal cartilage compared with the controls.Conclusions:The result of this study has shown, for the first time, that α5β1 integrin may be responsible for the induction of non-cartilaginous collagen expression in chondrocytes undergoing dedifferentiation. Again, this study has shown that the inhibition of ligand ligation to integrins may be an effective strategy to inhibit phenotypic change of cultured chondrocytes, and to improve the quality of matrix synthesized by primary cultured chondrocytes.

2. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors

M A Napier, S Bunting, M S Dennis, R A Lazarus, M T Lipari, W J Henzel, R M Pitti, T A Deisher Proc Natl Acad Sci U S A . 1990 Apr;87(7):2471-5. doi: 10.1073/pnas.87.7.2471.

The purification, complete amino acid sequence, and biological activity are described for several homologous snake venom proteins that are platelet glycoprotein (GP) IIb-IIIa antagonists and potent inhibitors of platelet aggregation. The primary structures of kistrin (from Agkistrodon rhodostoma), bitan (from Bitis arietans), three isoforms of trigramin (from Trimeresusus gramineus), and an isoform of echistatin (from Echis carinatus) were determined by automated sequence analysis and fast atom bombardment mass spectrometry analysis. Each of the protein in this family, which range from 47 to 83 residues, contains an Arg-Gly-Asp amino acid sequence found in protein ligands that binds to GPIIb-IIIa, a high (17 +/- 1%) cysteine content conserved in the primary sequence, and a homologous N-terminal region absent only in the echistatin isoforms. Each protein directly inhibits the interaction of purified platelet GPIIb-IIIa to immobilized fibrinogen about 100 times more effectively than does the pentapeptide Gly-Arg-Gly-Asp-Ser; IC50 values range from 1.1 to 3.0 nM. The IC50 value for the inhibition of platelet aggregation, using human platelet-rich plasma stimulated with ADP, ranges from 110 to 550 nM for the various proteins, about 1000-fold more potent than Gly-Arg-Gly-Asp-Ser. Kistrin binds reversibly to both resting and ADP-activated human platelets with high affinity (Kd = 10.8 nM and 1.7 nM, respectively) and to purified GPIIb-IIIa with a lower affinity (Kd = approximately 100 nM). Finally, kistrin injected at 1.0 mg/kg into rabbits reversibly inhibits platelet aggregation ex vivo over 30 min without induction of thrombocytopenia. We propose that these proteins are members of a general class of proteins found in the venom of pit vipers that inhibit platelet aggregation by antagonism of the GPIIb-IIIa-fibrinogen interaction and as such serve as potential antithrombotic agents.

3. Cell adhesion signaling regulates RANK expression in osteoclast precursors

Shigeru Tomoyasu, Ryutaro Kamijo, Masamichi Takami, Ayako Mochizuki, Yoichi Miyamoto, Sakae Tanaka, Yuho Kadono, Tsuyoshi Nakamaki, Tomio Inoue PLoS One . 2012;7(11):e48795. doi: 10.1371/journal.pone.0048795.

Cells with monocyte/macrophage lineage expressing receptor activator of NF-κB (RANK) differentiate into osteoclasts following stimulation with the RANK ligand (RANKL). Cell adhesion signaling is also required for osteoclast differentiation from precursors. However, details of the mechanism by which cell adhesion signals induce osteoclast differentiation have not been fully elucidated. To investigate the participation of cell adhesion signaling in osteoclast differentiation, mouse bone marrow-derived macrophages (BMMs) were used as osteoclast precursors, and cultured on either plastic cell culture dishes (adherent condition) or the top surface of semisolid methylcellulose gel loaded in culture tubes (non-adherent condition). BMMs cultured under the adherent condition differentiated into osteoclasts in response to RANKL stimulation. However, under the non-adherent condition, the efficiency of osteoclast differentiation was markedly reduced even in the presence of RANKL. These BMMs retained macrophage characteristics including phagocytic function and gene expression profile. Lipopolysaccharide (LPS) and tumor necrosis factor -αTNF-α activated the NF-κB-mediated signaling pathways under both the adherent and non-adherent conditions, while RANKL activated the pathways only under the adherent condition. BMMs highly expressed RANK mRNA and protein under the adherent condition as compared to the non-adherent condition. Also, BMMs transferred from the adherent to non-adherent condition showed downregulated RANK expression within 24 hours. In contrast, transferring those from the non-adherent to adherent condition significantly increased the level of RANK expression. Moreover, interruption of cell adhesion signaling by echistatin, an RGD-containing disintegrin, decreased RANK expression in BMMs, while forced expression of either RANK or TNFR-associated factor 6 (TRAF6) in BMMs induced their differentiation into osteoclasts even under the non-adherent condition. These results suggest that cell adhesion signaling regulates RANK expression in osteoclast precursors.