title: Neutralization of haemorrhagic activity of viper venoms by 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile.
abstract: Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 × 10(-9) (kcal/mol) without chelating Zn(2+) in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.
authors: Department of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, India.
authors: Kabburalli
authors: K
authors: Sunitha
authors: Mahadevappa
authors: M
authors: Hemshekhar
authors: Santosh Laxman
authors: SL
authors: Gaonkar
authors: Martin
authors: M
authors: Sebastin Santhosh
authors: Muthuvel
authors: M
authors: Suresh Kumar
authors: Basappa
authors: Babu Shubha
authors: BS
authors: Priya
authors: Kempaiah
authors: K
authors: Kemparaju
authors: Kanchugarakoppal Subbegowda
authors: KS
authors: Rangappa
authors: Shivananju
authors: S
authors: Nanjunda Swamy
authors: Kesturu Subbaiah
authors: KS
authors: Girish
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D015283:Citalopram / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011485:Protein Binding; D012867:Skin / Q000187:drug effects / Q000473:pathology; D014757:Viper Venoms / Q000037:antagonists & inhibitors* / Q000201:enzymology / Q000633:toxicity
chemical_list: C569214:1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile; D001572:Benzofurans; D004791:Enzyme Inhibitors; D014757:Viper Venoms; D015283:Citalopram; D010741:Phospholipases A