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 S10 . 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.

• Autores: Preciado Rojo, Lina María; Pereañez Jiménez, Jaime Andrés; Comer, Jeffrey
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2020
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/41067
• Acceso en línea: https://hdl.handle.net/10495/41067
• Palabra clave: Bothrops; Venenos de Crotálidos - enzimología; Crotalid Venoms - enzymology; Venenos de Crotálidos - toxicidad; Crotalid Venoms - toxicity; Edema - inducido químicamente; Edema - chemically induced; Edema - prevención & control; Edema - prevention & control; Hemorragia - inducido químicamente; Hemorrhage - chemically induced; Hemorragia - prevención & control; Hemorrhage - prevention & control; Ácidos Hidroxámicos - química; Hydroxamic Acids - chemistry; Ácidos Hidroxámicos - farmacología; Hydroxamic Acids - pharmacology; Inhibidores de la Metaloproteinasa de la Matriz - uso terapéutico; Matrix Metalloproteinase Inhibitors - therapeutic use; Metaloproteasas - toxicidad; Metalloproteases - toxicity; Ratones; Mice; Modelos Moleculares; Models, Molecular; Simulación de Dinámica Molecular; Molecular Dynamics Simulation; Peptidomiméticos - uso terapéutico; Peptidomimetics - therapeutic use; Fosfolipasas A2 - toxicidad; Phospholipases A2 - toxicity; Inhibidores de Proteasas - farmacología; Protease Inhibitors - pharmacology; Inhibidores de Proteasas - uso terapéutico; Protease Inhibitors - therapeutic use; Mordeduras de Serpientes - tratamiento farmacológico; Snake Bites - drug therapy; Mordeduras de Serpientes - patología; Snake Bites - pathology; Zinc - química; Zinc - chemistry; Zinc - farmacología; Zinc - pharmacology; https://id.nlm.nih.gov/mesh/D017837; https://id.nlm.nih.gov/mesh/D003435; https://id.nlm.nih.gov/mesh/D004487; https://id.nlm.nih.gov/mesh/D006470; https://id.nlm.nih.gov/mesh/D006877; https://id.nlm.nih.gov/mesh/D061965; https://id.nlm.nih.gov/mesh/D045726; https://id.nlm.nih.gov/mesh/D051379; https://id.nlm.nih.gov/mesh/D008958; https://id.nlm.nih.gov/mesh/D056004; https://id.nlm.nih.gov/mesh/D057786; https://id.nlm.nih.gov/mesh/D054467; https://id.nlm.nih.gov/mesh/D011480; https://id.nlm.nih.gov/mesh/D012909; https://id.nlm.nih.gov/mesh/D015032
• Rights: openAccess
• License: https://creativecommons.org/licenses/by/4.0/