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RGD-independent binding of Russell's Viper venom Kunitz-type protease inhibitors to platelet GPIIb/IIIa receptor.

ABSTRACT: This study elucidates the platelet-modulating properties of two snake venom Kunitz-type serine protease inhibitors, Rusvikunin and Rusvikunin-II, from Russell's Viper venom, their native and reconstituted complexes, and two synthetic custom peptides (developed from the platelet-binding region of Rusvikunin-II) against mammalian platelet-rich plasma (PRP) and washed platelets. The Rusvikunins and their complexes demonstrated concentration-dependent deaggregation and aggregation of washed platelets independent of von Willebrand factor and/or fibrinogen requirement. At lower concentrations they abolished collagen and ADP-induced platelet aggregation, but at higher concentrations, they progressively decreased the inhibition of ADP-induced aggregation and potentiated the effect of collagen on PRP. Rusvikunin complex/Rusvikunin-II bound to and induced RGD-independent aggregation of ?-chymotrypsin-treated platelets. Molecular docking studies suggested interaction of Rusvikunin-II and custom peptides with platelet GPIIb/IIIa receptor, which was validated by spectrofluorometry analysis and ELISA. This study reports, for the first time, an RGD-independent binding of a snake venom component to the platelet GPIIb/IIIa receptor.

SUBMITTER: Kalita B

PROVIDER: S-EPMC6549151 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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RGD-independent binding of Russell's Viper venom Kunitz-type protease inhibitors to platelet GPIIb/IIIa receptor.

Kalita Bhargab B Dutta Sumita S Mukherjee Ashis K AK

Scientific reports 20190605 1

This study elucidates the platelet-modulating properties of two snake venom Kunitz-type serine protease inhibitors, Rusvikunin and Rusvikunin-II, from Russell's Viper venom, their native and reconstituted complexes, and two synthetic custom peptides (developed from the platelet-binding region of Rusvikunin-II) against mammalian platelet-rich plasma (PRP) and washed platelets. The Rusvikunins and their complexes demonstrated concentration-dependent deaggregation and aggregation of washed platelet ...[more]

PMID: 31165757

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Project description:BackgroundSnakebite in India results in over 58,000 fatalities and a vast number of morbidities annually. The majority of these clinically severe envenomings are attributed to Russell's viper (Daboia russelii), which has a near pan-India distribution. Unfortunately, despite its medical significance, the influence of biogeography on the composition and potency of venom from disparate D. russelii populations, and the repercussions of venom variation on the neutralisation efficacy of marketed Indian antivenoms, remain elusive.MethodsHere, we employ an integrative approach comprising proteomic characterisation, biochemical analyses, pharmacological assessment, and venom toxicity profiling to elucidate the influence of varying ecology and environment on the pan-Indian populations of D. russelii. We then conducted in vitro venom recognition experiments and in vivo neutralisation assays to evaluate the efficacy of the commercial Indian antivenoms against the geographically disparate D. russelii populations.FindingsWe reveal significant intraspecific variation in the composition, biochemical and pharmacological activities and potencies of D. russelii venoms sourced from five distinct biogeographic zones across India. Contrary to our understanding of the consequences of venom variation on the effectiveness of snakebite therapy, commercial antivenom exhibited surprisingly similar neutralisation potencies against the majority of the investigated populations, with the exception of low preclinical efficacy against the semi-arid population from northern India. However, the ability of Indian antivenoms to counter the severe morbid effects of Daboia envenoming remains to be evaluated.ConclusionThe concerning lack of antivenom efficacy against the north Indian population of D. russelii, as well as against two other 'big four' snake species in nearby locations, underscores the pressing need to develop pan-India effective antivenoms with improved efficacy in high snakebite burden locales.

Dataset Information

RGD-independent binding of Russell's Viper venom Kunitz-type protease inhibitors to platelet GPIIb/IIIa receptor.

Publications

RGD-independent binding of Russell's Viper venom Kunitz-type protease inhibitors to platelet GPIIb/IIIa receptor.

Similar Datasets

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