Interaction between TNF and BmooMP-Alpha-I, a Zinc Metalloprotease Derived from Bothrops moojeni Snake Venom, Promotes Direct Proteolysis of This Cytokine: Molecular Modeling and Docking at a Glance

Abstract

Tumor necrosis factor (TNF) is a major cytokine in inflammatory processes and its deregulation plays a pivotal role in several diseases. Here, we report that a zinc metalloprotease extracted from Bothrops moojeni venom (BmooMP-alpha-I) inhibits TNF directly by promoting its degradation. This inhibition was demonstrated by both in vitro and in vivo assays, using known TLR ligands. These findings are supported by molecular docking results, which reveal interaction between BmooMP-alpha-I and TNF. The major cluster of interaction between BmooMP-alpha-I and TNF was confirmed by the structural alignment presenting Ligand Root Mean Square Deviation LRMS = 1.05 Å and Interactive Root Mean Square Deviation IRMS = 1.01 Å, this result being compatible with an accurate complex. Additionally, we demonstrated that the effect of this metalloprotease on TNF is independent of cell cytotoxicity and it does not affect other TLR-triggered cytokines, such as IL-12. Together, these results indicate that this zinc metalloprotease is a potential tool to be further investigated for the treatment of inflammatory disorders involving TNF deregulation.

Treatment with a Zinc Metalloprotease Purified from Bothrops moojeni Snake Venom (BmooMP-Alpha-I) Reduces the Inflammation in an Experimental Model of Dextran Sulfate Sodium-Induced Colitis

“…In our previous study, we investigated the role of BmooMP-alpha-I as a biological product able to hydrolyze the TNF cytokine, based mainly on in vitro experiments, as well as on modeling and docking approaches [18]. We concluded that this metalloprotease could be used to modulate of the inflammatory response, but this application would require further investigation, particularly when tested to treat inflammatory disorders involving the TNF cytokine.…”

“…Consequently, in the present study, we advanced in the process to characterize this metalloprotease as a modulator of the inflammatory response, by using an in vivo experimental design already applied in our group to assess an experimental inflammatory bowel disease [20]. Therefore, when compared with our previous studies [18, 20], it is necessary to emphasize that the present work investigated for the first time the use of the BmooMP-alpha-I metalloprotease to treat DSS-induced colitis.…”

“…The metalloprotease BmooMP-alpha-I was isolated and purified and its biological activity was assessed, as previously described [18]. The purified enzyme was diluted, dialyzed against 50 mM ammonium bicarbonate (pH 7.8), lyophilized, and stored at -20°C until used.…”

Antivenom Production against Bothrops jararaca and Bothrops erythromelas Snake Venoms Using Cross-Linked Chitosan Nanoparticles as an Immunoadjuvant

“…Thus, these venom proteins are fully trapped inside the polymer nanomatrix at the instant of nanoparticle cross-linking. Furthermore, that Bothrops venom has negatively charged peptides [ 9 , 61 ] can also explain the high loading efficiency. These results demonstrate the substantial ability of the optimized nanoparticle formulation to carry negatively charged proteins, maintaining colloidal stability, which is not common for particle-encapsulated proteins.…”

Bothrops moojeni Venom and Its Components Strongly Affect Osteoclasts’ Maturation and Protein Patterns

“…It is known that the venom is responsible for causing inflammation in several systems and models and triggers specific pathways and processes that can be a determinant of the OCs differentiation process [ 3 , 38 , 39 ]. Classically, this process depends on various inflammatory factors and needs a strictly balanced system, as changes in the membrane, receptors, and degradation of compounds can lead to several responses that influence differentiation [ 2 , 40 , 41 ]. B. moojeni venom’s effect is well known in human snakebite processes [ 42 , 43 , 44 ], which have not yet been reported in the OCs model, thus being totally exclusive and relevant data.…”