Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase

Abstract

Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), we tested the inhibitory activity of peptidomimetic compounds designed as inhibitors of matrix metalloproteinases on the activities of the SVMP Batx-I, from Bothrops atrox venom. The evaluated compounds show great potential for the inhibition of Batx-I proteolytic, hemorrhagic and edema-forming activities, especially the compound CP471474, a peptidomimetic including a hydroxamate zinc binding group. Molecular dynamics simulations suggest that binding of this compound to the enzyme is mediated by the electrostatic interaction between the hydroxamate group and the zinc cofactor, as well as contacts, mainly hydrophobic, between the side chain of the compound and amino acids located in the substrate binding subsites S1 and S1 ′ . These results show that CP471474 constitutes a promising compound for the development of co-adjuvants to neutralize local tissue damage induced by snake venom metalloproteinases.

Anti-Metalloprotease P-I Single-Domain Antibodies: Tools for Next-Generation Snakebite Antivenoms

“…Anti-BjussuMP-II VHH61 in particular showed specific binding of an amino acid from its CDR3 with Cys166, a component of this disulfide bridge. In this loop region, the presence of His154 can also be observed, represented as a zinc-binding motif, and together with the other histidines in the metalloproteinase domain, it is essential for catalytic activity [ 77 ]. The loop between the two α -helices also has the CIMP sequence, where a methionine residue (met-turn) is found, which is another structure in charge of maintaining the stability of the molecule, favoring the binding of His154 to zinc, as well as comprising a hydrophobic base for the active site of the groups [ 15 , 17 , 78 ].…”

Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms

“…In addition, this product also has other problems, such as mandatory administration in clinical facilities, poor cross-species neutralization, and limited efficacy in neutralizing local tissue damage induced by snake venoms, among others [ 16 , 17 ]. Therefore, new strategies to improve therapy access, such as venom characterization, antivenomic studies [ 34 ], humanized antibodies [ 35 ], and searching for small molecule inhibitors for snake venoms [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 36 ], have been performed.…”

“…Previously, this molecule was reported by its capacity to inhibit a PI-SVMP from B. atrox venom, demonstrating its ability to reduce the enzymatic and hemorrhagic activities induced by this toxin, with an IC 50 of 11.6 and 2.5 μM, respectively. In addition, the mode of action of this compound was described by molecular dynamic simulations, indicating that CP471474 interacts with the metalloproteinase substrate binding cleft [ 31 ].…”

Inflammatory Reaction Induced by Two Metalloproteinases Isolated from Bothrops atrox Venom and by Fragments Generated from the Hydrolysis of Basement Membrane Components

“…Escalante et al [5] tested the action of Batimastat, a broad-spectrum synthetic inhibitor of MMPs, in local damage induced by BaP1 and observed a reduction in bleeding, dermonecrosis and edema in mouse models. More recently, Preciado et al [37] demonstrated the efficacy of the synthetic CP 471474 inhibitor in edema induced by Batx-I, isolated from B. atrox venom. These observations indicate the relevance of catalytic activity for the proinflammatory activity of SVMPs.…”