A novel synthetic quinolinone inhibitor presents proteolytic and hemorrhagic inhibitory activities against snake venom metalloproteases

Abstract

Metalloproteases play a fundamental role in snake venom envenomation inducing hemorrhagic, fibrigen(ogen)olytic and myotoxic effects in their victims. Several snake venoms, such as those from the Bothrops genus, present important local effects which are not efficiently neutralized by conventional serum therapy. Consequently, these accidents may result in permanent sequelae and disability, creating economic and social problems, especially in developing countries, leading the attention of the World Health Organization that considered ophidic envenomations a neglected tropical disease. Aiming to produce an efficient inhibitor against bothropic venoms, we synthesized different molecules classified as quinolinones - a group of low-toxic chemical compounds widely used as antibacterial and antimycobacterial drugs - and tested their inhibitory properties against hemorrhage caused by bothropic venoms. The results from this initial screening indicated the molecule 2-hydroxymethyl-6-methoxy-1,4-dihydro-4-quinolinone (Q8) was the most effective antihemorrhagic compound among all of the assayed synthetic quinolinones. Other in vitro and in vivo experiments showed this novel compound was able to inhibit significantly the hemorrhagic and/or proteolytic activities of bothropic crude venoms and isolated snake venom metalloproteases (SVMPs) even at lower concentrations. Docking and molecular dynamic simulations were also performed to get insights into the structural basis of Q8 inhibitory mechanism against proteolytic and hemorrhagic SVMPs. These structural studies demonstrated that Q8 may form a stable complex with SVMPs, impairing the access of substrates to the active sites of these toxins. Therefore, both experimental and structural data indicate that Q8 compound is an interesting candidate for antiophidic therapy, particularly for the treatment of the hemorrhagic and necrotic effects induced by bothropic venoms.

Search for efficient inhibitors of myotoxic activity induced by ophidian phospholipase A2-like proteins using functional, structural and bioinformatics approaches

“…Thus, the search for simple and efficient inhibitors to complement serum therapy is a promising research area. In the last decade, a combination of functional, biochemical, biophysical, structural and bioinformatics tools have been used to test ligands that may be candidates to specifically inhibit ophidian venom compounds 17,19–25 .…”

Advances in the Therapeutic Application of Small-Molecule Inhibitors and Repurposed Drugs against Snakebite

“…Further in vitro and in vivo experiments in animal models demonstrated the significant inhibitory activity of this novel compound against the hemorrhagic and/or proteolytic activities of crude venoms of B. jararacussu , B. neuwiedi , B. moojeni , and B. alternatus . The same inhibitory activity was demonstrated against two isolated SVMPs (BjussuMP-I from B. jararacussu and neuwiedase from B. neuwiedi ) . The quinolinone compound 20 efficiently inhibited the hemorrhagic activities of the crude Bothropic venoms and BjussuMP-I at 1:10 (w/w, crude Bothropic venoms/BjussuMP-I: 20 ) in Swiss male mice.…”

“…Baraldi and co-workers synthesized and tested the inhibitory properties of quinolinones synthesized against Bothropic venoms; among them, compound 20 (Figure ) was found to be the most effective anti-hemorrhagic compound . Further in vitro and in vivo experiments in animal models demonstrated the significant inhibitory activity of this novel compound against the hemorrhagic and/or proteolytic activities of crude venoms of B. jararacussu , B. neuwiedi , B. moojeni , and B. alternatus .…”

Injúria renal e hemorragia em paciente vítima de acidente botrópico: relato de caso

“…Estudos têm sido desenvolvidos no sentido de desenvolver novos compostos para o tratamento de envenenamento ofídico, como o de Baraldi PT, et al (2016), que produziram um inibidor eficiente contra venenos botrópicos, ao sintetizarem diferentes moléculas classificadas como quinolinonas (grupo de compostos químicos de baixa toxidade amplamente utilizados como antibacterianos e antimicobacterianos) e e testarem suas propriedades inibidoras contra hemorragias causadas por esses venenos. Os resultados indicaram que a molécula 2-hidroximetil-6-metoxi-1,4-di-hidro-4-quinolinona (Q8) foi o composto antihemorrágico mais eficaz entre todas as quinolinonas sintéticas testadas, sendo capaz de inibir significativamente as atividades hemorrágicas e/ou proteolíticas de venenos brutos botrópicos e metaloproteases de veneno de serpentes isoladas, mesmo em concentrações mais baixas.…”