Pharmacological Control of Hyperproteolytic States in Blood by Synthetic Inhibitors of Serine Proteinases

Markwardt, Fritz

doi:10.1159/000214259

Cited by 6 publications

(7 citation statements)

References 2 publications

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“…This identity, however, does not extend to the P1 antiproteinase site at amino acid position 19 of the mature protein, which dictates specificity towards serine proteases. None of the variants in the Australian snakes contain the arginine residue present within Textilinins-1 and -2 and aprotinin which have been demonstrated to be necessary for plasmin and trypsin inhibition [10,30]. This is in keeping with the absence of plasmin inhibitory activity observed in the crude venom of all Australian snakes except for Oxyuranus and the Pseudonaja genera [11].…”

Section: Discussionmentioning

confidence: 70%

“…Note that multiple isoforms were identified in many of the snakes, with a high degree of identity within the propeptide leader sequence (a feature common to all Australian elapid toxin families) as well as complete conservation of cysteine residues involved in the formation of the three disulfide bonds. Interestingly, the arginine residue present at position 19 of the mature protein sequences of Textilinin-1 and -2, which plays a key role in the plasmin inhibitory effects of these toxins (as well as in the bovine homolog, Aprotinin), is absent from every other kunitz-type inhibitor cloned from the other Australian elapids [10,30]. Indeed, there is a significant degree of sequence variability within this region of the molecule, suggesting Australian snake venom kunitz-type inhibitors may have evolved to adopt a range of different activities.…”

Section: Resultsmentioning

confidence: 99%

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Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes

Pierre

Earl

Filippovich

et al. 2008

Cell. Mol. Life Sci.

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The venoms of Australian snakes contain a myriad of pharmacologically active toxin components. This study describes the identification and comparative analysis of two distinct toxin families, the kunitztype serine protease inhibitors and waprins, and demonstrates a previously unknown evolutionary link between the two. Multiple cDNA and full-length gene isoforms were cloned and shown to be composed of three exons separated by two introns. A high degree of identity was observed solely within the first exon which coded for the propeptide sequence and its cleavage site, and indicates that each toxin family has arisen from a gene duplication event followed by diversification only within the portion of the gene coding for the functional toxin. It is proposed that while the mechanism of toxin secretion is highly conserved, diversification of mature toxin sequences allows for the existence of multiple protein isoforms in the venom to adapt to variations within the prey environment.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes

Pierre

Earl

Filippovich

et al. 2008

Cell. Mol. Life Sci.

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“…Mutagenesis of this Arg to Ala leads to complete loss of activity for Txln 1 and 2 in the plasmin inhibitory assay. When the two cysteines are aligned, this arginine residue aligns with Arg‐15 in aprotinin, which has been suggested to form part of the active plasmin inhibitory region (Markwardt, 1978). Thus, together with other residues, Arg‐19 appears to be critical for maintaining an active structure, as has been suggested by others (Powers & Harper, 1986).…”

Section: Discussionmentioning

confidence: 99%

A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties

et al. 2002

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Summary. Two peptides, textilinins 1 and 2, isolated from the venom of the Australian common brown snake, Pseudonaja textilis textilis, are effective in preventing blood loss. To further investigate the potential of textilinins as antihaemorrhagic agents, we cloned cDNAs encoding these proteins. The isolated full-length cDNA (430 bp in size) was shown to code for a 59 amino acid protein, corresponding in size to the native peptide, plus an additional 24 amino acid propeptide. Six such cDNAs were identified, differing in nucleotide sequence in the coding region but with an identical propeptide. All six sequences predicted peptides containing six conserved cysteines common to Kunitz-type serine protease inhibitors. When expressed as glutathione S-transferase (GST) fusion proteins and released by cleavage with thrombin, only those peptides corresponding to textilinin 1 and 2 were active in inhibiting plasmin with K i values similar to those of their native counterparts and in binding to plasmin less tightly than aprotinin by two orders of magnitude. Similarly, in the mouse tail vein blood loss model only recombinant textilinin 1 and 2 were effective in reducing blood loss. These recombinant textilinins have potential as therapeutic agents for reducing blood loss in humans, obviating the need for reliance on aprotinin, a bovine product with possible risk of transmissible disease, and compromising the fibrinolytic system in a less irreversible manner.

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“…The major milestone in this field was the breakthrough achieved in determining the crystal structure of thrombin. The availability of this structure together with the elucidation of structural features of hirudin provides a rational basis for the design and synthesis of peptide and nonpeptide thrombin inhibitors [15][16][17][18].…”

Section: Synthetic Thrombin Inhibitorsmentioning

confidence: 99%

Historical Perspective of the Development of Thrombin Inhibitors

Markwardt¹

2002

Pathophysiol Haemos Thromb

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Progress in molecular biology has stimulated interest in the structure and function of thrombin. It has improved our understanding of its central role in thrombogenesis and has clarified the molecular events of inhibitor binding. This development has resulted in the production of recombinant hirudins and hirudin analogues. It has also allowed the molecular design of synthetic antithrombins, and encouraged the development of these products for clinical use. All pharmacological aspects speak in favor of the use of direct thrombin inhibitors as antithrombotic agents, especially in the potential indications where thrombin plays a crucial pathogenetic role. If their apparent advantages compared with heparin can be definitely demonstrated, the direct thrombin inhibitors may become the drug of choice for certain indications.

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Pharmacological Control of Hyperproteolytic States in Blood by Synthetic Inhibitors of Serine Proteinases

Cited by 6 publications

References 2 publications

Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes

Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes

A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties

Historical Perspective of the Development of Thrombin Inhibitors

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