Newton001 Proof-of concept screen to counteract Bothrops toxins targeting tissue cohesion

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute


In Brazil, the considerable human morbidity and mortality caused by accidents with poisoning animals pose high public health, economical and societal costs. Snakebite is a major occupational hazard, and rural subsistent farming communities are the main sufferers from this condition. Bothrops species are responsible for more than 20,000 accidents per year in Brazil, corresponding to 90% of all recorded snakebites. Bothrops spp. envenomation is characterized by prominent local tissue damage, including haemorrhage, necrosis and oedema as well as disturbance in the blood coagulation system. Since 1920's, immunotherapy by anti-venoms is the only efficacious treatment for snakebites accidents approved by WHO (World Health Organization). Yet, it has important limitations and side-effects, including inability to prevent local damage at the snakebite site and anaphylatic shock in some patients. Thus, there is an unmet clinical need to develop novel pharmacological therapies that can counteract snake venoms and/or be used as coadjuvant therapy with anti-venoms.

Understanding how the snake venom interfaces with cellular events important for tissue homeostasis is instrumental to inform novel therapies Yet, the molecular and cellular aspects of envenomation are poorly understood. This is in spite of extensive efforts from different labs in Brazil to characterise the biochemical properties of specific toxins and their in vivo consequences in animal models. The aim of the current Research Partnership from the Newton Fund/CONFAP is to (i) set up and optimise a screen to identify likely therapeutic candidates to facilitate cellular response to injury by Bothrops venom and (ii) develop novel techniques suitable to dissect mechanisms of snake envenomation.

Driven by unique strengths of the co-applicants in venom biochemistry and cellular signalling, this proposal will identify leads for drug development with important clinical implications for treatment of envenomation patients.

Technical Summary

The proposed collaboration will increase our knowledge of mechanisms of action of toxins, which allows us to elucidate how the cell operates during envenomation. We will set up a screen to demonstrate the proof of principle that endogenous pathways are perturbed by Bothrops toxins and that inhibitors can be identified using this methodology. Within the time-frame of 12 months and focusing on cell-cell cohesion integrity phenotype, we propose to:

1. design and optimize a screen using primary cells (assays, readout, quantitative and statistical analysis);
2. identify which purified fractions of Bothrops venom targets cell cohesion;
3. validate results with inhibitors and specific identified targets;
4. provide extensive technical and conceptual training in screen, cell biology and signalling.

Planned Impact



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Lopes-De-Souza L (2019) Development of a cell-based in vitro assay as a possible alternative for determining bothropic antivenom potency. in Toxicon : official journal of the International Society on Toxinology

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Schultz F (2019) Cardiomyocyte-myofibroblast contact dynamism is modulated by connexin-43. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Stransky S (2018) In vitro assessment of cytotoxic activities of Lachesis muta muta snake venom. in PLoS neglected tropical diseases

Description We identified five FDA approved drugs that protect primary cells against damage caused by envenomation.
Exploitation Route Further drug screens to optimize the responses of currently identified drugs.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

Description We initiated a collaboration with AstraZeneca to perform further drug screens
First Year Of Impact 2018
Sector Pharmaceuticals and Medical Biotechnology
Description Pathfinder Award
Amount £113,642 (GBP)
Funding ID 201054/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 12/2017
Title in vitro system to study envenomation 
Description Optimized a methodology for biochemical an cell biology analysis of venom perturbations leading to cell death 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact this methodology will bring about important mechanisms on how snake toxin injure cellular processes. 
Description Carlos Chavez 
Organisation Federal University of Minas Gerais
Department Dept of Biochemistry and Immunology
Country Brazil 
Sector Academic/University 
PI Contribution We provided a cellular model to investigate different actions of snake venoms in cell structure and funcitonality.
Collaborator Contribution Prof Chavez provided expertise in the identification of binding domains for protein-protein interactions using peptides spotted onto membranes. We also collaborate closely in understanding the mechanisms of snake envenomation in cells.
Impact Manuscript submitted McCormack, JJ; Bruche,S; Ouadda, ABD; Ishii, H; Lu,H; Garcia-Cattaneo,A; Chávez-Olórtegui,C; Lamarche-Vane, N & Braga, VMM. The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts.
Start Year 2012
Title "In vitro methods for the determination of anti-venom potency: kit and its use" 
Description A background patent has been jointly filed between the Federal University of Minas Gerais (Brazil) and Imperial Innovations. This patent covers the assay technology which will be enable the screening proposed under this project. It claims a method to test the neutralizing potency of anti-Bothropic serum in vitro based on cell cultures. More specifically the method consists of the determination of ED50 (Effective Dose, 50%) in cells from the snake B. jararaca previously neutralized by anti-bothropic sera. The patent enables newly produced anti-sera in horses to be tested in order to determine their neutralizing potency of those anti-venoms and select for future use for the treatment of bite accidents by snakes of the genus Bothrops. 
IP Reference BR1020150264437 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact It is possible that additional method of use IP may arise under this proposal and Imperial Innovations, with UFMG, will work towards assessing and filing patents on such novel IP.
Description Debate "Career progress following PhD studies" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Debate organize by the Brazil Forum at Imperial College London and aimed to provide advice and discussion on key steps to move forward in academic career
Year(s) Of Engagement Activity 2017
Description Debate at Meeting organised by the Association of Brazilian Post-docs 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Discussion about career progression in academia
Year(s) Of Engagement Activity 2016
Description Talk at Brazilian Embassy Networking event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Workshop "Innovation in Healthcare" - discussion on engagement and collaborations - how is it best fomented?
Year(s) Of Engagement Activity 2017
Description Workshop Women in Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Women Scientists discussing their career progression in Academia, what worked well, what could have been different
Year(s) Of Engagement Activity 2009
Description presentation "Leaders in Innovation Fellowships - Royal Academy of Engineering and FAPESP" - Brazilian Embassy, London - U.K. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Workshop to define better engagement with the Brazilian Diaspora in UK
Year(s) Of Engagement Activity 2019