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Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges

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ABSTRACT

The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using “gold-standard” methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted.

No MeSH data available.


Research milestones on natural inhibitors of metalloendopeptidases. The investigation on the natural resistance that some animals presented to snake venoms began in the eighteenth century. Since Fontana’s pioneering work, the field has grown considerably. Researchers have managed to purify several inhibitors from the sera of snakes and mammals and determined their relevant physicochemical properties. The challenges that lie ahead are the three-dimensional structure elucidation of these snake venom metalloendopeptidase inhibitors (SVMPIs) in their free and toxin-complexed forms in order to better understand the molecular dynamics of this interaction.
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toxins-08-00250-f001: Research milestones on natural inhibitors of metalloendopeptidases. The investigation on the natural resistance that some animals presented to snake venoms began in the eighteenth century. Since Fontana’s pioneering work, the field has grown considerably. Researchers have managed to purify several inhibitors from the sera of snakes and mammals and determined their relevant physicochemical properties. The challenges that lie ahead are the three-dimensional structure elucidation of these snake venom metalloendopeptidase inhibitors (SVMPIs) in their free and toxin-complexed forms in order to better understand the molecular dynamics of this interaction.

Mentions: During the second half of the 20th century, a large portion of the research in this field has been devoted to the isolation of SVMPIs for further physicochemical and chemical characterizations, including primary structure determination. However, over the last 15 years, the main goal of natural resistance research shifted from protein purification to mechanistic studies in an attempt to understand the interaction between inhibitors and target toxins at the molecular level. This review does not intend to present all known SVMPIs and their determined characteristics; this information can be found by the reader in a historical series of reviews [20,21,24,26,27,28,29]. In fact, with this contribution, we aimed to summarize the available knowledge in the field of SVMPIs (Figure 1) and to discuss novel perspectives in this research area, especially on how to address the actual bottleneck due to the lack of information on the three-dimensional structures of SVMPIs (Figure 2).


Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges
Research milestones on natural inhibitors of metalloendopeptidases. The investigation on the natural resistance that some animals presented to snake venoms began in the eighteenth century. Since Fontana’s pioneering work, the field has grown considerably. Researchers have managed to purify several inhibitors from the sera of snakes and mammals and determined their relevant physicochemical properties. The challenges that lie ahead are the three-dimensional structure elucidation of these snake venom metalloendopeptidase inhibitors (SVMPIs) in their free and toxin-complexed forms in order to better understand the molecular dynamics of this interaction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037476&req=5

toxins-08-00250-f001: Research milestones on natural inhibitors of metalloendopeptidases. The investigation on the natural resistance that some animals presented to snake venoms began in the eighteenth century. Since Fontana’s pioneering work, the field has grown considerably. Researchers have managed to purify several inhibitors from the sera of snakes and mammals and determined their relevant physicochemical properties. The challenges that lie ahead are the three-dimensional structure elucidation of these snake venom metalloendopeptidase inhibitors (SVMPIs) in their free and toxin-complexed forms in order to better understand the molecular dynamics of this interaction.
Mentions: During the second half of the 20th century, a large portion of the research in this field has been devoted to the isolation of SVMPIs for further physicochemical and chemical characterizations, including primary structure determination. However, over the last 15 years, the main goal of natural resistance research shifted from protein purification to mechanistic studies in an attempt to understand the interaction between inhibitors and target toxins at the molecular level. This review does not intend to present all known SVMPIs and their determined characteristics; this information can be found by the reader in a historical series of reviews [20,21,24,26,27,28,29]. In fact, with this contribution, we aimed to summarize the available knowledge in the field of SVMPIs (Figure 1) and to discuss novel perspectives in this research area, especially on how to address the actual bottleneck due to the lack of information on the three-dimensional structures of SVMPIs (Figure 2).

View Article: PubMed Central - PubMed

ABSTRACT

The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using “gold-standard” methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted.

No MeSH data available.