Ana Gisele C. Neves-Ferreira
Laboratório de Toxinologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil

Protein inhibitors of peptidases are widely distributed among animals, plants and
microorganisms. They are important regulatory molecules that function to avoid
proteolysis in various biological systems. From the plasma of animals that are naturally resistant to snake envenomation, a special class of peptidase inhibitors has been identified. These inhibitors have antihemorrhagic properties and form inactive noncovalent complexes with snake venom metallopeptidases. In non-resistant animals, these toxic metallopeptidases induce microvascular damage and are responsible for systemic and local hemorrhage, key events in the pathogenesis of viperid envenomation. The inhibitors isolated from mammalian plasma are grouped into the MEROPS I43 family of immunoglobulin-related proteins; those from reptiles show a typical cystatin-like fold and belong to the MEROPS I25C subfamily. The inhibitors show a reversible tight-binding reaction mechanism of inhibition, although due to a lack of three-dimensional information
for the enzyme-inhibitor complexes, the structural features that govern the interaction are largely unknown. The talk will highlight the latest advances in the field, analyzing future perspectives in the area of natural immunity against snake venom. Several mass spectrometry-based strategies that are currently being used to gain insights into the molecular determinants of selective metallopeptidase inhibition will be presented. The wide range of natural toxin inhibitors may constitute a rich source of information leading to new possibilities in intervention not only against snake venom metallopeptidases but also against other metzincins, such as mammalian MMPs and ADAMs.