Статья

Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile

Kabburalli SunithaDepartment of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, IndiaMahadevappa HemshekharDepartment of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, IndiaSantosh L. GaonkarDepartment of Studies in Chemistry, University of Mysore, Mysore, Karnataka, IndiaM. Sebastin SanthoshDepartment of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, IndiaMuthuvel Suresh KumarCenter for Bioinformatics, Pondicherry University, Pondicherry, IndiaBasappa BasappaDepartment of Chemistry, Bangalore University, Bangalore, Karnataka, IndiaB.S. PriyaDepartment of Studies in Chemistry, University of Mysore, Mysore, Karnataka, IndiaKempaiah KemparajuDepartment of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, IndiaKanchugarakoppal S. RangappaDepartment of Studies in Chemistry, University of Mysore, Mysore, Karnataka, IndiaS. Nanjunda SwamyKesturu S. GirishDepartment of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, India

2011en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1111/j.1742-7843.2011.00725.x

Цитирования и источники

Цитирований: 2Использованных источников: 0

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