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

Albulescu, Laura-Oana; Xie, Cuicui; Ainsworth, Stuart; Alsolaiss, Jaffer; Crittenden, Edouard; Dawson, Charlotte A.; Softley, Rowan; Bartlett, Keirah E.; Harrison, Robert A.; Kool, Jeroen; Casewell, Nicholas R.

doi:10.1038/s41467-020-19981-6

Cited by 104 publications

(170 citation statements)

References 63 publications

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“…Future work should undertake head-tohead comparisons between Prinomastat and DMPS using the presently used methodology and with a larger species pool (including Echis) to ascertain if DMPS consistently performs less efficiently than Prinomastat. However, in another study DMPS was conspicuously unable to neutralize Daboia russelii venom (155), which exerts its powerfully procoagulant effect via SVMPinduced Factor X activation like the neonate C. culminatus venom in this study. This suggests two future hypotheses to test.…”

Section: Discussioncontrasting

confidence: 63%

A Clot Twist: Extreme Variation in Coagulotoxicity Mechanisms in Mexican Neotropical Rattlesnake Venoms

et al. 2021

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Rattlesnakes are a diverse clade of pit vipers (snake family Viperidae, subfamily Crotalinae) that consists of numerous medically significant species. We used validated in vitro assays measuring venom-induced clotting time and strength of any clots formed in human plasma and fibrinogen to assess the coagulotoxic activity of the four medically relevant Mexican rattlesnake species Crotalus culminatus, C. mictlantecuhtli, C. molossus, and C. tzabcan. We report the first evidence of true procoagulant activity by Neotropical rattlesnake venom in Crotalus culminatus. This species presented a strong ontogenetic coagulotoxicity dichotomy: neonates were strongly procoagulant via Factor X activation, whereas adults were pseudo-procoagulant in that they converted fibrinogen into weak, unstable fibrin clots that rapidly broke down, thereby likely contributing to net anticoagulation through fibrinogen depletion. The other species did not activate clotting factors or display an ontogenetic dichotomy, but depleted fibrinogen levels by cleaving fibrinogen either in a destructive (non-clotting) manner or via a pseudo-procoagulant mechanism. We also assessed the neutralization of these venoms by available antivenom and enzyme-inhibitors to provide knowledge for the design of evidence-based treatment strategies for envenomated patients. One of the most frequently used Mexican antivenoms (Bioclon Antivipmyn®) failed to neutralize the potent procoagulant toxic action of neonate C. culminatus venom, highlighting limitations in snakebite treatment for this species. However, the metalloprotease inhibitor Prinomastat substantially thwarted the procoagulant venom activity, while 2,3-dimercapto-1-propanesulfonic acid (DMPS) was much less effective. These results confirm that venom-induced Factor X activation (a procoagulant action) is driven by metalloproteases, while also suggesting Prinomastat as a more promising potential adjunct treatment than DMPS for this species (with the caveat that in vivo studies are necessary to confirm this potential clinical use). Conversely, the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) inhibited the direct fibrinogen cleaving actions of C. mictlantecuhtli venom, thereby revealing that the pseudo-procoagulant action is driven by kallikrein-type serine proteases. Thus, this differential ontogenetic variation in coagulotoxicity patterns poses intriguing questions. Our results underscore the need for further research into Mexican rattlesnake venom activity, and also highlights potential limitations of current antivenom treatments.

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Section: Discussioncontrasting

confidence: 63%

A Clot Twist: Extreme Variation in Coagulotoxicity Mechanisms in Mexican Neotropical Rattlesnake Venoms

et al. 2021

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“…Therefore, a general target-based approach would help to treat the major clinical profiles of envenomation. For example, small molecule inhibitors specific against svMP (Batimastat and Marimastat), PLA 2 (Varespladib) or svSP (Nafamostat), the three most common toxin families in Viperinae, were already successfully tested against certain viperid venoms [ 15 , 220 , 221 , 222 ]. However, for many new potential antivenom therapies, clinical trials for their use against snakebites have not yet been carried out.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, snakebite envenomation affect over 2.7 million people per year, which gives snakebites a great medical importance and concomitantly more global attention [ 12 , 13 , 14 ]. Among the most dangerous true vipers, in terms of highest mortality, are the African Bitis arietans (puff adder) and Echis ocellatus (West African saw-scaled viper), as well as two of India’s ‘Big Four’, namely, Echis carinatus (Asian saw-scaled viper) and Daboia russelii (Russell’s viper) [ 12 , 15 ]. Nevertheless, viperid bites are also a critical health issue in the Middle East and even Europe [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Old World Vipers—A Review about Snake Venom Proteomics of Viperinae and Their Variations

Damm

Hempel

Süssmuth

2021

Toxins

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Fine-tuned by millions of years of evolution, snake venoms have frightened but also fascinated humanity and nowadays they constitute potential resources for drug development, therapeutics and antivenoms. The continuous progress of mass spectrometry techniques and latest advances in proteomics workflows enabled toxinologists to decipher venoms by modern omics technologies, so-called ‘venomics’. A tremendous upsurge reporting on snake venom proteomes could be observed. Within this review we focus on the highly venomous and widely distributed subfamily of Viperinae (Serpentes: Viperidae). A detailed public literature database search was performed (2003–2020) and we extensively reviewed all compositional venom studies of the so-called Old-World Vipers. In total, 54 studies resulted in 89 venom proteomes. The Viperinae venoms are dominated by four major, four secondary, six minor and several rare toxin families and peptides, respectively. The multitude of different venomics approaches complicates the comparison of venom composition datasets and therefore we differentiated between non-quantitative and three groups of quantitative workflows. The resulting direct comparisons within these groups show remarkable differences on the intra- and interspecies level across genera with a focus on regional differences. In summary, the present compilation is the first comprehensive up-to-date database on Viperinae venom proteomes and differentiating between analytical methods and workflows.

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“…Examples of these novel alternatives are: human monoclonal antibody with different types of antibody formats i.e. whole IgG, single-chain variable fragments (scFvs), antigen binding fragments (Fabs and F(ab') 2 ) (12), oligonucleotide aptamers (13), inhibitors of enzymatic toxins (14), inhibitors of phospholipases A 2 (15), inhibitors of snake venom proteases (16,17), inhibitors of hyaluronidase (18), metal chelators (19)(20)(21) and neuronal acetylcholine receptor (nAChR) mimetics (22). All of these represent promising and interesting alternative therapeutic modalities to improve or replace PDAV, increase effectiveness, cause less adverse effects, and be cheaper to produce.…”

Section: Introductionmentioning

confidence: 99%

A Quest for a Universal Plasma-Derived Antivenom Against All Elapid Neurotoxic Snake Venoms

Ratanabanangkoon

2021

Front. Immunol.

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This review describes the research aimed at the development of universal antivenom against elapid neurotoxic snake venoms. The antivenoms produced in Thailand in the 1980s were of low potency, especially against the elapid venoms. This was thought to be due to the low immunogenicity of the α-neurotoxins, which are the most lethal toxins in these venoms. Comparisons of various α-neurotoxin conjugates and polymers, and also different immunological adjuvants, showed that the adjuvant used is the major determinant in the antibody response in horses. The potent Freund’s adjuvant was not used due to its severe local side-effect in horses. Therefore, a novel immunization protocol termed ‘low dose, low volume multi-site’ was developed for use in horses. This immunization protocol has led to the production of highly potent monospecific antivenoms against several elapid and viperid venoms, and two potent polyspecific antivenoms, one against 4 neurotoxic and another against 3 hematotoxic venoms. The immunization protocol has also led to other improvements in antivenom production including: several fold increases in antiserum potency, a reduction in the time required to reach therapeutically useful antibody titers, a 90% reduction in the amount of venom used, and 100% of the horses responding to the immunization program. This development is partly responsible for significant decrease in the Thailand’s annual snakebite death toll from a few dozens to mostly nil in recent years. Finally, a simple and novel immunization strategy, using a ‘diverse toxin repertoire’ composed of numerous elapid toxin fractions as immunogen, was proposed and tested. This immunization procedure has resulted in the successful production of a widely paraspecific antiserum against at least 36 neurotoxic venoms of 28 species encompassing 10 genera and from 20 countries on four continents, and possibly against all elapid venoms with α-neurotoxins as the lethal toxins. These results indicate that, with optimizations of the composition of the ‘diverse toxin repertoire’, the immunization scheme and antibody fractionation to increase the antivenom neutralizing potency, an effective universal antivenom against the neurotoxic elapid snakes of the world can be produced.

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

Cited by 104 publications

References 63 publications

A Clot Twist: Extreme Variation in Coagulotoxicity Mechanisms in Mexican Neotropical Rattlesnake Venoms

A Clot Twist: Extreme Variation in Coagulotoxicity Mechanisms in Mexican Neotropical Rattlesnake Venoms

Old World Vipers—A Review about Snake Venom Proteomics of Viperinae and Their Variations

A Quest for a Universal Plasma-Derived Antivenom Against All Elapid Neurotoxic Snake Venoms

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