title: Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges.
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.
authors: Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil. vivika.bastos@gmail.com.|National Institute of Science and Technology on Toxins (INCTTOX), CNPq, Brasilia 71605-001, Brazil. vivika.bastos@gmail.com.
authors: Viviane A
authors: VA
authors: Bastos
authors: Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil. gomes.netof@gmail.com.|National Institute of Science and Technology on Toxins (INCTTOX), CNPq, Brasilia 71605-001, Brazil. gomes.netof@gmail.com.
authors: Francisco
authors: F
authors: Gomes-Neto
authors: Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil. jperales@ioc.fiocruz.br.|National Institute of Science and Technology on Toxins (INCTTOX), CNPq, Brasilia 71605-001, Brazil. jperales@ioc.fiocruz.br.
authors: Jonas
authors: J
authors: Perales
authors: Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil. jonasperales@gmail.com.|National Institute of Science and Technology on Toxins (INCTTOX), CNPq, Brasilia 71605-001, Brazil. jonasperales@gmail.com.
authors: Ana Gisele C
authors: AG
authors: Neves-Ferreira
authors: Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil. richardhemmi@gmail.com.|National Institute of Science and Technology on Toxins (INCTTOX), CNPq, Brasilia 71605-001, Brazil. richardhemmi@gmail.com.
authors: Richard H
authors: RH
authors: Valente
mesh_terms: D000818:Animals; D000931:Antidotes / Q000266:history / Q000627:therapeutic use*; D049671:History, 18th Century; D049672:History, 19th Century; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000266:history / Q000378:metabolism; D011480:Protease Inhibitors / Q000266:history / Q000627:therapeutic use*; D011487:Protein Conformation; D030162:Reptilian Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000266:history / Q000378:metabolism; D012909:Snake Bites / Q000188:drug therapy* / Q000201:enzymology / Q000266:history; D012910:Snake Venoms / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000201:enzymology / Q000266:history; D013329:Structure-Activity Relationship
chemical_list: D000931:Antidotes; D011480:Protease Inhibitors; D030162:Reptilian Proteins; D012910:Snake Venoms; D008666:Metalloendopeptidases
keywords: cross-linking; hydrogen/deuterium exchange; mass spectrometry; metalloendopeptidase inhibitor; modeling; natural immunity; natural resistance; snake venom; structure; therapeutic application