Snake venoms are attractive for drug discovery and development, with a number of therapeutics derived from snake venom either in clinical use or in development. Recognising this opportunity, Australian biopharmaceutical company QRxPharma Ltd and its subsidiary Venomics Pty Ltd (VPL) has partnered with the University of Queensland (UQ) to screen and develop drug candidates from Australian elapid snake venoms. VPL has three haemostasis candidates in early preclinical development. Textilinin-1 (Q8008) is a 7 kDa potent and selective plasmin inhibitor that has application as an anti-fibrinolytic agent to reduce blood loss associated with complex surgeries. Haempatch™ (Q8009) is a Factor Xa-like protein that displays potent procoagulant effects and is being developed as a topical haemostatic agent to reduce blood loss resulting from surgery or trauma. CoVase™ (V0801) is a procoagulant cofactor that may have application as a systemic anti-bleeding agent in the treatment of internal bleeding and non-compressible haemorrhage. This review focuses on drug discovery from Australian elapid snake venoms, with emphasis on the QRxPharma/VPL drug discovery project undertaken in collaboration with UQ and candidates at further stages of development.
"Kunitz-type peptides from venomous animals adopt a conserved structural fold with diverse biological functions, which are an important source of lead drug candidates towards human plasmin (Girard et al., 1989; Ranasinghe and McManus, 2013). Some Kunitz-type toxin peptides have been found to have potent human plasmin inhibitory activities, such as textilinin-1 from snake venom, AvKTI from spider venom, and Bi- KTI from bee venom (Choo et al., 2012; Earl et al., 2012; Flight et al., 2005; Wan et al., 2013). However, no Kunitz-type plasmin inhibitor from scorpion venom has been characterized. "
[Show abstract][Hide abstract] ABSTRACT: Kunitz-type peptides from venomous animals are an important source of lead drug candidates towards human plasmin, a target of protease-associated diseases. However, no Kunitz-type plasmin inhibitor from venomous scorpion has been characterized. Here, we first investigated plasmin inhibiting activities of eight known Kunitz-type scorpion toxins Hg1, BmKTT-1, BmKTT-2, BmKTT-3, LmKTT-1a, LmKTT-1b, LmKTT-1c and BmKPI, and found a new plasmin inhibitor BmKTT-2, a Kunitz-type toxin peptide from the scorpion Buthus martensi karch. Protease inhibitory activity assay showed that BmKTT-2 potently inhibited plasmin with a Ki value of 8.75 ± 2.05 nM. Structure-function relationship studies between BmKTT-2 and plasmin showed that BmKTT-2 is a classical Kunitz-type plasmin inhibitor: Lys13 in BmKTT-2 is the P1 site, and Ala14 in BmKTT-2 is the P1' site. Interestingly, BmKTT-2 has potent inhibiting activities towards three important digestive serine proteases trypsin, chymotrypsin and elastase, suggesting a good stability for administering oral medications. To the best of our knowledge, BmKTT-2 is the first Kunitz-type human plasmin inhibitor from scorpion venom, providing novel insights into drug developments targeting human plasmin protease.
"Therefore, target specificity of toxins is of paramount importance . Since these toxins have evolved over millions of years of evolutionary time to rapidly and systematically breakdown prey homeostasis, they are invaluable as investigational ligands in elucidating physiological pathways or as lead compounds in drug design and therapeutics [4,5,6,7,8]. "
[Show abstract][Hide abstract] ABSTRACT: Despite the unparalleled diversity of venomous snakes in Australia, research has concentrated on a handful of medically significant species and even of these very few toxins have been fully sequenced. In this study, venom gland transcriptomes were sequenced from eleven species of small Australian elapid snakes, from eleven genera, spanning a broad phylogenetic range. The particularly large number of sequences obtained for three-finger toxin (3FTx) peptides allowed for robust reconstructions of their dynamic molecular evolutionary histories. We demonstrated that each species preferentially favoured different types of α-neurotoxic 3FTx, probably as a result of differing feeding ecologies. The three forms of α-neurotoxin [Type I (also known as (aka): short-chain), Type II (aka: long-chain) and Type III] not only adopted differential rates of evolution, but have also conserved a diversity of residues, presumably to potentiate prey-specific toxicity. Despite these differences, the different α-neurotoxin types were shown to accumulate mutations in similar regions of the protein, largely in the loops and structurally unimportant regions, highlighting the significant role of focal mutagenesis. We theorize that this phenomenon not only affects toxin potency or specificity, but also generates necessary variation for preventing/delaying prey animals from acquiring venom-resistance. This study also recovered the first full-length sequences for multimeric phospholipase A2 (PLA2) 'taipoxin/paradoxin' subunits from non-Oxyuranus species, confirming the early recruitment of this extremely potent neurotoxin complex to the venom arsenal of Australian elapid snakes. We also recovered the first natriuretic peptides from an elapid that lack the derived C-terminal tail and resemble the plesiotypic form (ancestral character state) found in viper venoms. This provides supporting evidence for a single early recruitment of natriuretic peptides into snake venoms. Novel forms of kunitz and waprin peptides were recovered, including dual domain kunitz-kunitz precursors and the first kunitz-waprin hybrid precursors from elapid snakes. The novel sequences recovered in this study reveal that the huge diversity of unstudied venomous Australian snakes are of considerable interest not only for the investigation of venom and whole organism evolution but also represent an untapped bioresource in the search for novel compounds for use in drug design and development.
[Show abstract][Hide abstract] ABSTRACT: Kunitz-type protease inhibitors, which consist of around 60 amino acid residues and three distinctive disulfide bridges, exhibit a broad range of physiological functions such as protease inhibitor and ion channel blocker. In this study, we identified cDNAs encoding Kunitz-type protease inhibitors, Pr-mulgins 1, 2 and 3, from the venom gland cDNA library of Papuan pigmy mulga snake (New Guinean Pseudechis australis). The deduced amino acid sequences of the Pr-mulgins are 92.4-99.3% identical with their orthologs in Australian P. australis. Pr-mulgin proteins were recombinantly prepared and subjected to inhibitory assays against proteases. Pr-mulgin 1 significantly affected matrix metalloprotease (MMP) 2; Pr-mulgins 2 and 3 showed potent inhibition to trypsin and plasma plasmin; and Pr-mulgin 2 inhibited α-chymotrypsin. Pr-mulgins 1, 2, and 3, however, had essentially no effect on Drosophila K(+) channels (Shaker) and rat K(+) channels (K(v) 1.1).
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