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.
Highlights
Snake bite envenoming is a major public health problem, which the World Health Organization has recognized as a Category A neglected tropical disease since 2017 [1]
The metalloproteinase Batx-I from B. atrox venom exhibits weak hemorrhagic activity and lacks coagulant and defibrinating activity, but it is able to induce a mild myonecrosis. This metalloproteinase may contribute to the hemorrhage and local tissue damage observed in patients envenomed by B. atrox from Colombia [32,33], since it constitutes about the 45%
Batx-I hemorrhagic activity is similar to the activity reported for other P-I type
Summary
Snake bite envenoming is a major public health problem, which the World Health Organization has recognized as a Category A neglected tropical disease since 2017 [1]. Envenoming causes mortality and morbidity mainly in tropical and subtropical areas, such as sub-Saharan Africa, South and Southeast. Papua New Guinea and Latin America [2], with annual deaths estimated at 100,000 and sequelae in more than 400,000 cases [3]. In Latin America, recent estimates suggest about 57,500 annual envenomings, with an incidence of 6.2 per 100,000 people [2]. In Colombia 5434 cases were reported in 2018, with an incidence of 10.9 per 100,000 people [4]. It is estimated that snakes of the Bothrops genus (Viperidae), B. asper and B. atrox, cause about 70–90% of all envenomings in Colombia.
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