Structure of Thrombin Inhibited by Aeruginosin 298-A from a Blue-Green Alga

Steiner, Jorge L. Rios; Murakami, Masahirô; Tulinsky, A.

doi:10.1021/ja973038t

Cited by 55 publications

(63 citation statements)

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“…), [11][12][13][14] aeruginosin 298-A, aeruginosins 98-A and 98-B (from the blue-green alga Microcystis aeruginosa). [15][16][17] On the other hand, many compounds having benzamidine or arginine moiety as a partial structure have been synthesized and their inhibitory effects on thrombin examined. [18][19][20][21][22][23] Argatroban (MD-805) proposed by Okamoto et al 18) is one of most potent synthetic thrombin inhibitors (K i ϭ1.9ϫ10 Ϫ8 M) and is clinically used.…”

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confidence: 99%

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Toyota

Sekizaki

Takahashi

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Thrombin is a trypsin-like serine proteinase that plays a critical role in the blood coagulation cascade. Thrombin converts fibrinogen into fibrin which forms part of the blood clot, 1,2) and activates other blood coagulation factors such as V, VIII, XIII, and protein C.3) Moreover, thrombin also activates blood platelets, 4,5) and acts as a mitogen for various cell types. [6][7][8] Thus, thrombin has become a special target in the design and development of antithrombotic agents.Various naturally occurring thrombin inhibitors have been found: hirudin (from the leech Hirudo medicinalis), 9,10) cyclotheonamide A, B, and nazumamide A (from the marine sponge Theonella sp.), [11][12][13][14] aeruginosin 298-A, aeruginosins 98-A and 98-B (from the blue-green alga Microcystis aeruginosa). [15][16][17] On the other hand, many compounds having benzamidine or arginine moiety as a partial structure have been synthesized and their inhibitory effects on thrombin examined. [18][19][20][21][22][23] Argatroban (MD-805) proposed by Okamoto et al. 18) is one of most potent synthetic thrombin inhibitors (K i ϭ1.9ϫ10 Ϫ8 M) and is clinically used. Complexes of human or bovine a-thrombin with synthetic arginyl peptides have been analyzed by X-ray diffraction studies. [24][25][26][27][28][29][30] The X-ray data suggested that the thrombin active site consists of the specificity (S1) pocket, the hydrophobic proximal pocket (P-pocket), and the hydrophobic distal pocket (D-pocket). The guanidino nitrogen atoms of inhibitors form a salt bridge with Asp189 (numbering of the thrombin amino acid residues is based on the chymotrypsinogen nomenclature introduced by Bode et al.) 24,28) in S1 pocket, and additional favorable interactions between the inhibitor and D-pocket or P-pocket enhance the inhibitory potency.Cationic organic molecules such as benzamidine and phenylguanidine derivatives are potent inhibitors of trypsin and trypsin-like enzymes, [31][32][33] owing to the electrostatic interaction between the cationic group of inhibitor and an anionic residue at S1 site in the trypsin active site. It is known that salicylaldehyde spontaneously forms a very stable Schiff base metal chelate with an a-amino acid and metal ion. Therefore, we designed and synthesized amidino-or guanidino-containing Schiff base metal chelates (Chart 1) as trypsin-like enzyme inhibitors. [34][35][36] The manifold compounds in the series of A and B can be prepared by changing the combination of salicylaldehyde derivatives, various aamino acids, and metal ions, respectively.Recently we proposed a new binding mode between trypsin active site and amidino-containing Schiff base metal chelate by X-ray diffraction study.37) The cationic amidino group of chelates was shown to form a salt bridge with the carboxylate of Asp189 in the S1 pocket of trypsin as expected. In addition, it was evidenced that the metal ion and the phenolic oxygen of the Schiff base contribute additional interactions with His57 and Ser195 of trypsin.In this report, the inhibitory effect of amidin...

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confidence: 99%

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Toyota

Sekizaki

Takahashi

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…1). The L-Leu originally thought to be present in aeruginosin 298-A [7] was later found to be D-Leu (see below). The aeruginosins are believed to bind to thrombin in a similar manner to D-Phe-Pro-Arg chloromethyl ketone, with the hydrophobic Leu or Phe group occupying the S 3 subsite, the octahydroindole backbone interacting at the S 2 subsite, and the guanidine terminus mimicking the arginine at the S 3 subsite.…”

Section: Aeruginosinsmentioning

confidence: 99%

“…The structures of several members have been elucidated by detailed NMR, by degradative studies, and other methods. For example, the structure and absolute configuration of aeruginosin 298-A 1 was determined by X-ray crystal analysis as a ternary complex bound to hirugen-thrombin at a resolution of 2.1 Å [7]. The structure of aeruginosin 98-B 3 was elucidated as a complex bound to trypsin also by X-ray crystallography [8].…”

Section: Aeruginosinsmentioning

confidence: 99%

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New and Old Challenges in Total Synthesis. From Concept to Practice

et al. 2003

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“…There is one further water-mediated interaction in the trypsin-complex, namely a hydrogen bond between the phenolic hydroxyl of Hpla, the amide NH of Cys220, and the carbonyl oxygen of Ser146.The sulfate moiety protrudes into the solvent in opposite direction to trypsin -however, at the corresponding place of thrombin it would rise into the hydrophobic pocket (Tyr60A/Trp60D), a very unfavorable position.Therefore one can attribute a discriminating role to the sulfate group that results in poor thrombin inhibition compared to the inhibition of trypsin. On the other hand another cyanopeptide -aeruginosin 298-A (5, Figure 1) -shows unexpected interactions with thrombin in the ternary hirugen-thrombin complex [14]. One of several surprising interactions is the gentle displacement of the 60 insertion loops caused by Choi's six-membered ring.…”

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confidence: 99%

New Cyanopeptide‐Derived Low MolecularWeight Thrombin Inhibitors

Radau¹,

Gebel²,

Rauh³

2003

Archiv der Pharmazie

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Thrombosis is the result of defective regulation of the hemostasis system. This cardiovascular disorder may lead to deep vein thrombosis, myocardial infarction, and stroke. The majority of current drug research is focused on finding inhibitors of thrombin - the global player in hemostasis. In our work, we emphasize investigation of the marine environment to yield new lead structures from marine organisms like blue-green algae (cyanobacteria). This article deals with the design, syntheses, and inhibition tests of new low molecular weight thrombin inhibitors utilizing cyanopeptides, the secondary metabolites of cyanobacteria with interesting biological activities, as new lead structures. Starting with aeruginosin 98-B (2) as a lead structure, we have developed and synthesized new, selective acting inhibitors of thrombin (RA-1001 and RA-1002), which are suitable targets for further structure-activity studies.

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Structure of Thrombin Inhibited by Aeruginosin 298-A from a Blue-Green Alga

Cited by 55 publications

References 32 publications

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

New and Old Challenges in Total Synthesis. From Concept to Practice

New Cyanopeptide‐Derived Low MolecularWeight Thrombin Inhibitors

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