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Snake venom proteome of Protobothrops mucrosquamatus in Taiwan: Delaying venom-induced lethality in a rodent model by inhibition of phospholipase A2 activity with varespladib.
J Proteomics. 2021 03 15; 234:104084.JP

Abstract

Protobothrops mucrosquamatus, also known as the brown spotted pit viper or Taiwanese habu, is a medically significant venomous snake in Taiwan, especially in the northern area. To more fully understand the proteome profile of P. mucrosquamatus, we characterized its venom composition using a bottom-up proteomic approach. Whole venom components were fractionated by RP-HPLC and then analyzed by SDS-PAGE. Each protein band in gels was excised and subjected to protein identification by LC-MS/MS. A subsequent proteomic analysis revealed the presence of 61 distinct proteins belonging to 19 families in P. mucrosquamatus venom. Snake venom metalloproteinase (SVMP; 29.4%), C-type lectin (CLEC; 21.1%), snake venom serine protease (SVSP; 17.6%) and phospholipase A2 (PLA2; 15.9%) were the most abundant protein families, whereas several low-abundance proteins, categorized into eight protein families, were demonstrated in P. mucrosquamatus venom for the first time. Because PLA2 is known to make a major contribution to venom lethality, we evaluated whether the known PLA2 inhibitor, varespladib, was capable of preventing the toxic effects of P. mucrosquamatus venom. This small-molecule drug demonstrated the ability to inhibit PLA2 activity in vitro (IC50 = 101.3 nM). It also blunted lethality in vivo, prolonging survival following venom injection in a mouse model, but it showed limited potency against venom-induced local hemorrhage in this model. Our findings provide essential biological and pathophysiological insights into the composition of P. mucrosquamatus venom and suggest PLA2 inhibition as an adjunctive or alternative therapeutic strategy in the clinical management of P. mucrosquamatus envenoming in emergency medicine.

SIGNIFICANCE:

P. mucrosquamatus envenomation is a significant medical concern in Taiwan, especially in the northern region. Although antivenom is commonly used for rescuing P. mucrosquamatus envenoming, severe clinical events still occur, with more than 20% of cases requiring surgical intervention. Small-molecule therapy offers several advantages as a potential adjunctive, or even alternative, to antivenom treatment, such as heat stability, low antigenicity and ease of administration, among others. A deeper understanding of the venom proteome of P. mucrosquamatus would aid in the discovery of small-molecule drugs that could be repurposed to target specific venom proteins. Here, we applied a bottom-up proteomic approach to characterize the protein profile of P. mucrosquamatus venom. Varespladib, a small-molecule drug used to treat inflammatory disease, was repurposed to inhibit the toxicity of P. mucrosquamatus venom, and was shown to reduce the lethal effects of P. mucrosquamatus envenomation in a rodent model. Varespladib might be used as a first-aid therapeutic against P. mucrosquamatus envenoming in the pre-referral period and/or as an adjunctive agent administered together with anti-P. mucrosquamatus antivenom.

Authors+Show Affiliations

Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.Department of Emergency Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.Faculty of Biotechnology and Laboratory Science in Medicine, School of Medical Technology and Engineering, National Yang-Ming University, Taipei, Taiwan.Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.Department of Emergency Medicine, En Chu Kong Hospital, New Taipei City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.Department of Emergency Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: master198012@gmail.com.Department of Emergency Medicine, Yeezen General Hospital, Taoyuan, Taiwan. Electronic address: m9337@yeezen.com.tw.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33359941

Citation

Liu, Chien-Chun, et al. "Snake Venom Proteome of Protobothrops Mucrosquamatus in Taiwan: Delaying Venom-induced Lethality in a Rodent Model By Inhibition of Phospholipase A2 Activity With Varespladib." Journal of Proteomics, vol. 234, 2021, p. 104084.
Liu CC, Wu CJ, Hsiao YC, et al. Snake venom proteome of Protobothrops mucrosquamatus in Taiwan: Delaying venom-induced lethality in a rodent model by inhibition of phospholipase A2 activity with varespladib. J Proteomics. 2021;234:104084.
Liu, C. C., Wu, C. J., Hsiao, Y. C., Yang, Y. H., Liu, K. L., Huang, G. J., Hsieh, C. H., Chen, C. K., & Liaw, G. W. (2021). Snake venom proteome of Protobothrops mucrosquamatus in Taiwan: Delaying venom-induced lethality in a rodent model by inhibition of phospholipase A2 activity with varespladib. Journal of Proteomics, 234, 104084. https://doi.org/10.1016/j.jprot.2020.104084
Liu CC, et al. Snake Venom Proteome of Protobothrops Mucrosquamatus in Taiwan: Delaying Venom-induced Lethality in a Rodent Model By Inhibition of Phospholipase A2 Activity With Varespladib. J Proteomics. 2021 03 15;234:104084. PubMed PMID: 33359941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Snake venom proteome of Protobothrops mucrosquamatus in Taiwan: Delaying venom-induced lethality in a rodent model by inhibition of phospholipase A2 activity with varespladib. AU - Liu,Chien-Chun, AU - Wu,Cho-Ju, AU - Hsiao,Yung-Chin, AU - Yang,Ya-Han, AU - Liu,Kuei-Lin, AU - Huang,Guo-Jen, AU - Hsieh,Cheng-Hsien, AU - Chen,Chun-Kuei, AU - Liaw,Geng-Wang, Y1 - 2020/12/25/ PY - 2020/09/30/received PY - 2020/12/01/revised PY - 2020/12/20/accepted PY - 2020/12/29/pubmed PY - 2020/12/29/medline PY - 2020/12/28/entrez KW - P. mucrosquamatus venom KW - Phospholipase A(2) KW - Small molecule therapy KW - Varespladib KW - Venom proteome SP - 104084 EP - 104084 JF - Journal of proteomics JO - J Proteomics VL - 234 N2 - Protobothrops mucrosquamatus, also known as the brown spotted pit viper or Taiwanese habu, is a medically significant venomous snake in Taiwan, especially in the northern area. To more fully understand the proteome profile of P. mucrosquamatus, we characterized its venom composition using a bottom-up proteomic approach. Whole venom components were fractionated by RP-HPLC and then analyzed by SDS-PAGE. Each protein band in gels was excised and subjected to protein identification by LC-MS/MS. A subsequent proteomic analysis revealed the presence of 61 distinct proteins belonging to 19 families in P. mucrosquamatus venom. Snake venom metalloproteinase (SVMP; 29.4%), C-type lectin (CLEC; 21.1%), snake venom serine protease (SVSP; 17.6%) and phospholipase A2 (PLA2; 15.9%) were the most abundant protein families, whereas several low-abundance proteins, categorized into eight protein families, were demonstrated in P. mucrosquamatus venom for the first time. Because PLA2 is known to make a major contribution to venom lethality, we evaluated whether the known PLA2 inhibitor, varespladib, was capable of preventing the toxic effects of P. mucrosquamatus venom. This small-molecule drug demonstrated the ability to inhibit PLA2 activity in vitro (IC50 = 101.3 nM). It also blunted lethality in vivo, prolonging survival following venom injection in a mouse model, but it showed limited potency against venom-induced local hemorrhage in this model. Our findings provide essential biological and pathophysiological insights into the composition of P. mucrosquamatus venom and suggest PLA2 inhibition as an adjunctive or alternative therapeutic strategy in the clinical management of P. mucrosquamatus envenoming in emergency medicine. SIGNIFICANCE: P. mucrosquamatus envenomation is a significant medical concern in Taiwan, especially in the northern region. Although antivenom is commonly used for rescuing P. mucrosquamatus envenoming, severe clinical events still occur, with more than 20% of cases requiring surgical intervention. Small-molecule therapy offers several advantages as a potential adjunctive, or even alternative, to antivenom treatment, such as heat stability, low antigenicity and ease of administration, among others. A deeper understanding of the venom proteome of P. mucrosquamatus would aid in the discovery of small-molecule drugs that could be repurposed to target specific venom proteins. Here, we applied a bottom-up proteomic approach to characterize the protein profile of P. mucrosquamatus venom. Varespladib, a small-molecule drug used to treat inflammatory disease, was repurposed to inhibit the toxicity of P. mucrosquamatus venom, and was shown to reduce the lethal effects of P. mucrosquamatus envenomation in a rodent model. Varespladib might be used as a first-aid therapeutic against P. mucrosquamatus envenoming in the pre-referral period and/or as an adjunctive agent administered together with anti-P. mucrosquamatus antivenom. SN - 1876-7737 UR - https://www.unboundmedicine.com/medline/citation/33359941/Snake_venom_proteome_of_Protobothrops_mucrosquamatus_in_Taiwan:_Delaying_venom_induced_lethality_in_a_rodent_model_by_inhibition_of_phospholipase_A2_activity_with_varespladib_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1874-3919(20)30452-8 DB - PRIME DP - Unbound Medicine ER -