Desmoteplase: discovery, insights and opportunities for ischaemic stroke

Abstract

Nature has provided a vast array of bioactive compounds that have been exploited for either diagnostic or therapeutic use. The field of thrombosis and haemostasis in particular has enjoyed much benefit from compounds derived from nature, notably from snakes and blood-feeding animals. Indeed, the likelihood that blood-feeding animals would harbour reagents with relevant pharmacology and with potential pharmaceutical benefit in haemostasis was not too far-fetched. Blood-feeding animals including leeches and ticks have evolved a means to keep blood from clotting or to at least maintain the liquid state, and some of these have been the subject of clinical development. A more recent example of this has been the saliva of the common vampire bat Desmodus rotundus, which has proven to harbour a veritable treasure trove of novel regulatory molecules. Among the bioactive compounds present is a fibrinolytic compound that was shown over 40 years ago to be a potent plasminogen activator. Studies of this vampire bat-derived plasminogen activator, more recently referred to as desmoteplase, revealed that this protease shared a number of structural and functional similarities to the human fibrinolytic protease, tissue-type plasminogen activator (t-PA) yet harboured critically important differences that have rendered this molecule attractive for clinical development for patients with ischaemic stroke. AbbreviationsBBB, blood-brain barrier; DIAS trial, Desmoteplase in Acute Stroke trial; DSPAa1, desmoteplase (also referred to as Desmodus salivary plasminogen activator); ICH, intracerebral haemorrhage; LDLR, low-density lipoprotein receptor; LRP-1, low-density lipoprotein-related receptor-1; NMDAR, NMDA receptor; PAI-1, plasminogen activator inhibitor type 1; PDGF-CC, platelet derived growth factor-CC; sct-PA, single-chain tissue-type plasminogen activator; t-PA, tissue-type plasminogen activator; tct-pA, two chain tissue-type plasminogen activator IntroductionBlood clotting is an essential phenomenon that is not only required to initiate the vascular repair processes but also provides the first line defence of the innate immune system. Activation of the blood coagulation cascade ultimately results in the cleavage of fibrinogen into fibrin, which polymerizes and forms the structural component of a clot to maintain clot rigidity and stability. The haemostatic system maintains a fine balance between clot formation and clot dissolution. Clots formed under normal conditions are necessarily shortlived and removed in a timely manner by another endogenous enzyme cascade referred to as the fibrinolytic system (Cesarman-Maus and Hajjar, 2005). The effector enzyme of this system is the serine protease, plasmin which is generated from its zymogenic precursor, plasminogen, by the plasminogen activators. There are two such plasminogen activators, both serine proteases, known as urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA).The fibrinolytic system is conserved among all warmblooded species studied to da...

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

“…Actually, the only molecule that has been molecularly and functionally characterized so far in bat saliva is the plasminogen activator desmoteplase, which has been tested in clinical trials as a thrombolytic for the treatment of ischemic stroke. 21 More recently, the first comprehensive transcriptome analysis and proteome studies of D. rotundus submaxillary glands were reported.…”

“…In contrast, prothrombinase was not inhibited when reactions were started with prothrombin/Desmolaris (not shown, n 5 4). It has been reported that Protein S enhances FXa inhibition by TFPI in the presence of phosphatidylcholine/phosphatidylserine/phosphatidylethanolamine and Ca 21 . 29,30 Although Protein S (0-160 nM) increases the inhibition of FXa (0.5 nM) by TFPI, no change was observed with Desmolaris (10 nM) (not shown).…”

Towards Effective and Safe Thrombolysis and Thromboprophylaxis

“…Still the gold standard therapy for acute ischemic stroke, 36 tPA is neurotoxic, 25 and the use of urokinase or desmoteplase avoids these complications inherent to tPA. 37,38 This has the potential to widen the currently very narrow therapeutic window for stroke thrombolysis of 3 to 4 hours. 6 The truncated, low-molecular-weight form scuPA is the preferred entity over full-length urokinase because it provides a smaller size with improved thrombus accessibility, no immunogenicity, and similar fibrinolytic potency.…”

Pharmacological Treatment of Acute Ischemic Stroke: A Review

“…Recently multicentre trial proved the safety and feasibility of tenecteplase in patient with minor strokes 26 . Fourth generation thrombolytic, desmoteplase is a highly fibrin-specific plasminogen thrombolytic agent, is the recombinant version of the plasminogen activator derived from the saliva of a vampire bat 27 . An in-vitro study show the variation with alteplase, desmoteplase does not increase blood brain barrier (BBB) permeability.…”