Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Steven R. Hall; Sean A. Rasmussen; Edouard Crittenden; Charlotte A. Dawson; Keirah E. Bartlett; Adam P. Westhorpe; Laura Oana Albulescu; Jeroen Kool; José María Gutiérrez; Nicholas R. Casewell

doi:10.1038/s41467-023-43510-w

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Steven R. Hall, Sean A. Rasmussen, Edouard Crittenden, Charlotte A. Dawson, Keirah E. Bartlett, Adam P. Westhorpe, Laura Oana Albulescu, Jeroen Kool, José María Gutiérrez, Nicholas R. Casewell^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

Original language	English
Article number	7812
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-43510-w
Publication status	Published - 14 Dec 2023

Bibliographical note

Funding Information:
We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funding Information:
We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Publisher Copyright:
© 2023, The Author(s).

Funding

We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funders	Funder number
Valerie Tilston
Wellcome Trust	221712/Z/20/Z
Wellcome Trust
Medical Research Council	MR/S00016X/1, MC_PC_15040
Medical Research Council
Royal Society	200517/Z/16/Z
Royal Society
University of Liverpool	NIF\R1\192161
University of Liverpool

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Hall, S. R., Rasmussen, S. A., Crittenden, E., Dawson, C. A., Bartlett, K. E., Westhorpe, A. P., Albulescu, L. O., Kool, J., Gutiérrez, J. M., & Casewell, N. R. (2023). Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. Nature Communications, 14, 1-15. Article 7812. https://doi.org/10.1038/s41467-023-43510-w

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abstract = "Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.",

author = "Hall, {Steven R.} and Rasmussen, {Sean A.} and Edouard Crittenden and Dawson, {Charlotte A.} and Bartlett, {Keirah E.} and Westhorpe, {Adam P.} and Albulescu, {Laura Oana} and Jeroen Kool and Guti{\'e}rrez, {Jos{\'e} Mar{\'i}a} and Casewell, {Nicholas R.}",

note = "Funding Information: We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM{\textquoteright}s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM{\textquoteright}s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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AU - Hall, Steven R.

AU - Rasmussen, Sean A.

AU - Crittenden, Edouard

AU - Dawson, Charlotte A.

AU - Bartlett, Keirah E.

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AU - Albulescu, Laura Oana

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AU - Gutiérrez, José María

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N1 - Funding Information: We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We would like to give our thanks to Paul Rowley for maintaining the snakes at the LSTM’s herpetarium and for routine venom extractions, Dr. Cassandra Modahl and Dr. Amy Marriott for their help with animal welfare observations during the in vivo experimentation, and Valerie Tilston and her team at the University of Liverpool for preparing the histopathology slides. The Authors acknowledge use of the Biomedical Services Unit provided by Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool. Funding was provided by a (i) Newton International Fellowship (NIF\R1\192161) from the Royal Society to S.R.H., (ii) a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and the Royal Society to N.R.C., (iii) a Wellcome Trust funded project grant (221712/Z/20/Z) to N.R.C. and J.K., (iv) a UK Medical Research Council research grant (MR/S00016X/1) to N.R.C. and (v) a UK Medical Research Council funded Confidence in Concept Award (MC_PC_15040) to N.R.C. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2023, The Author(s).

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N2 - Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

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Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

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