RESUMO
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.
Assuntos
Antídotos/uso terapêutico , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Proteínas de Répteis/antagonistas & inibidores , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/antagonistas & inibidores , Animais , Antídotos/história , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Metaloendopeptidases/química , Metaloendopeptidases/história , Metaloendopeptidases/metabolismo , Inibidores de Proteases/história , Conformação Proteica , Proteínas de Répteis/química , Proteínas de Répteis/história , Proteínas de Répteis/metabolismo , Mordeduras de Serpentes/enzimologia , Mordeduras de Serpentes/história , Venenos de Serpentes/química , Venenos de Serpentes/enzimologia , Venenos de Serpentes/história , Relação Estrutura-AtividadeRESUMO
In 1923 Karl H. Slotta obtained his PhD in chemistry from the University of Breslau, Germany, where he continued to work. At the instigation of the gynaecologist Ludwig Fraenkel, Slotta made the first isolation of progesterone in 1933. In 1934 he proposed the correct structural formula. Slotta was appointed professor of chemistry in 1935, but with the oppression of the Nazi regime mounting, he soon left Germany with his family to take a post at the Instituto Butantan, Brazil. Initially he worked on the chemistry of coffee. In 1938 Slotta and his brother-in-law Heinz Fraenkel-Conrat isolated crotoxin from Crotalus durissus terrificus venom, the first snake toxin to be obtained in crystalline form. They had evidence to suggest that the toxicity of crotoxin was due to a phospholipolytic action on nerve lipids. In 1938 Slotta's department was closed; he subsequently cofounded a biopharmaceutical company. In 1956 Slotta was appointed research professor of biochemistry at the University of Miami, USA. Slotta purified the most basic polypeptide from Naja naja venom, known as direct lytic factor, and with James Vick identified this as cardiotoxin. Karl H. Slotta will be remembered not only for his skill as a biochemist but also for his indomitable and cheerful spirit.
Assuntos
Bioquímica/história , Venenos de Serpentes/história , Toxicologia/história , Brasil , Café/química , Café/história , Crotoxina/química , Crotoxina/história , Crotoxina/toxicidade , Alemanha , História do Século XX , Venenos de Serpentes/químicaRESUMO
Maurício Rocha e Silva is well known as the discoverer of bradykinin, the powerful hypotensive and smooth muscle stimulating polypeptide which was first detected in plasma following the addition of Bothrops jararaca venom. The discovery in São Paulo, Brazil, in 1948 was the outcome of studies on proteolytic enzymes that Rocha e Silva started in 1939 at a time when circulatory shock was considered to be mediated by histamine. This line of research was prompted by the publications of Feldberg and Kellaway which identified the release of histamine and a slow-reacting substance (SRC-C) from isolated lungs perfused with Naja venom. Rocha e Silva was interested in determining whether trypsin-like enzymes, as shown for phospholipase, had a role in the release of histamine in shock. Instead, he and his co-workers demonstrated that such an enzyme released a new autopharmacological principle, bradykinin, from a plasma globulin precursor. Studies by Ferreira and Rocha e Silva on ways of blocking plasma kinin-destroying activity led Ferreira to isolate bradykinin-potentiating peptides from B. jararaca venom. These peptides were later shown to block angiotensin-I converting enzyme and so have an effect on hypertension. The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins.