Phylovenomics of Daboia russelii across the Indian subcontinent. Bioactivities and comparative in vivo neutralization and in vitro third-generation antivenomics of antivenoms against venoms from India, Bangladesh and Sri Lanka

Plá, Davinia; Sanz, Libia; Quesada-Bernat, Sarai; Villalta, Mauren; Baal, Joshua; Chowdhury, Mohammad Abdul Wahed; León, Guillermo; Gutiérrez, José Marı́a; Kuch, Ulrich; Calvete, Juan J.

doi:10.1016/j.jprot.2019.103443

Cited by 74 publications

(84 citation statements)

References 111 publications

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“…While DMPS remains a promising future therapeutic for snakebite, not least because of its oral formulation, licensed drug status and decades of therapeutic use for other indications 61,62 , it seems unlikely to be highly efficacious as a solo therapy against a wide variety of different snake species due to only targeting SVMP toxins 28 . Contrastingly, the combination of marimastat and varespladib reported here provided consistent and prolonged preclinical protection against lethality caused by a wide diversity of medically important vipers despite, for example, the south Asian Russell's viper (D. russelii) having substantially different abundances of distinct venom toxins to that of E. ocellatus 4,[63][64][65] (Fig. 1).…”

Section: Discussionmentioning

confidence: 69%

A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

et al. 2020

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Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.

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Section: Discussionmentioning

confidence: 69%

A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

et al. 2020

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“…We therefore advise against assuming that the preclinical efficacy of an antivenom against a venom from one region can be simply extrapolated to other regions. The dangers of such assumptions are apparent from the variable preclinical efficacy of Russell’s viper ( Daboia russelii ) antivenoms manufactured with venom sourced from India against venoms from Bangladesh, Pakistan and Sri Lanka [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…Due to the method of manufacture, antivenom effectiveness is largely restricted to the venom/s used for animal immunisation [4,5]. Differences in venom composition can vary substantially between species, and even between different locales of the same species [6][7][8]. The geographic origin of venom immunogens can therefore influence the geographic effectiveness of antivenoms [9].…”

Section: Introductionmentioning

confidence: 99%

An analysis of preclinical efficacy testing of antivenoms for sub-Saharan Africa: Inadequate independent scrutiny and poor-quality reporting are barriers to improving snakebite treatment and management

et al. 2020

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Background The World Health Organization's strategy to halve snakebite mortality and morbidity by 2030 includes an emphasis on a risk-benefit process assessing the preclinical efficacy of antivenoms manufactured for sub-Saharan Africa. To assist this process, we systematically collected, standardised and analysed all publicly available data on the preclinical efficacy of antivenoms designed for sub-Saharan Africa. Methodology/Principal findings Using a systematic search of publication databases, we focused on publicly available preclinical reports of the efficacy of 16 antivenom products available in sub Saharan Africa. Publications since 1999 reporting the industry standard intravenous pre-incubation method of murine in vivo neutralisation of venom lethality (median effective dose [ED 50 ]) were included. Eighteen publications met the criteria. To permit comparison of the several different reported ED 50 values, it was necessary to standardise these to microlitre of antivenom resulting in 50% survival of mice challenged per milligram of venom (μl/mg). We were unable to identify publicly available preclinical data on four antivenoms, whilst data for six polyspecific antivenoms were restricted to a small number of venoms. Only four antivenoms were tested against a wide range of venoms. Examination of these studies for the reporting of key metrics required for interpreting antivenom ED 50 s were highly variable, as evidenced by eight different units being used for the described ED 50 values. Conclusions/Significance There is a disturbing lack of (i) preclinical efficacy testing of antivenom for sub Saharan Africa, (ii) publicly available reports and (iii) independent scrutiny of this medically important data. Where reports do exist, the methods and metrics used are highly variable. This

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“…Due to variation in toxin constituents among saw-scaled vipers [ 13 ], these antivenoms proved to be highly ineffective, which resulted in case fatality rates increasing from b2% with species-appropriate antivenom to 10-12% [ 61 , 62 ]. In South Asia, antivenom manufactured using Indian Russell’s viper ( Daboia russelii ) venom exhibits low neutralizing potencies against venom from Bangladeshi populations of the same species, suggesting that perhaps five to ten times the normal treatment dose might be needed for effective treatment [ 15 ]. Contrastingly, antivenom made in Thailand against the congeneric species Daboia siamensis appears to exhibit considerable cross-recognition of venoms from the same species found in distinct geographical locales [ 63 ].…”

Section: Therapeutic Consequences Of Venom Variationmentioning

confidence: 99%

Causes and Consequences of Snake Venom Variation

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Laustsen

et al. 2020

Trends in Pharmacological Sciences

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Snake venoms are mixtures of toxins that vary extensively between and within snake species. This variability has serious consequences for the management of the world’s 1.8 million annual snakebite victims. Advances in ‘omic’ technologies have empowered toxinologists to comprehensively characterize snake venom compositions, unravel the molecular mechanisms that underpin venom variation, and elucidate the ensuing functional consequences. In this review, we describe how such mechanistic processes have resulted in suites of toxin isoforms that cause diverse pathologies in human snakebite victims and we detail how variation in venom composition can result in treatment failure. Finally, we outline current therapeutic approaches designed to circumvent venom variation and deliver next-generation treatments for the world’s most lethal neglected tropical disease.

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Phylovenomics of Daboia russelii across the Indian subcontinent. Bioactivities and comparative in vivo neutralization and in vitro third-generation antivenomics of antivenoms against venoms from India, Bangladesh and Sri Lanka

Cited by 74 publications

References 111 publications

A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

An analysis of preclinical efficacy testing of antivenoms for sub-Saharan Africa: Inadequate independent scrutiny and poor-quality reporting are barriers to improving snakebite treatment and management

Causes and Consequences of Snake Venom Variation

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