A Small-Molecule Inhibitor of Nipah Virus Envelope Protein-Mediated Membrane Fusion

Abstract

Nipah virus (NiV), a highly pathogenic paramyxovirus, causes respiratory disease in pigs and severe febrile encephalitis in humans with high mortality rates. On the basis of the structural similarity of viral fusion (F) proteins within the family Paramyxoviridae, we designed and tested 18 quinolone derivatives in a NiV and measles virus (MV) envelope protein-based fusion assay beside evaluation of cytotoxicity. We found five compounds successfully inhibiting NiV envelope protein-induced cell fusion. The most active molecules (19 and 20), which also inhibit the syncytium formation induced by infectious NiV and show a low cytotoxicity in Vero cells, represent a promising lead quinolone-type compound structure. Molecular modeling indicated that compound 19 fits well into a particular protein cavity present on the NiV F protein that is important for the fusion process.

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity

“…Molecular modelling indicated that one compound fitted well into a cavity present in the NiV F protein. This compound inhibited NiV-induced cell fusion but not MV-induced cell fusion, thus underlining specific differences between morbillivirus and henipavirus F proteins (Niedermeier et al, 2009).…”

“…They interfere with the conformational changes of the F protein at the beginning of the fusion process (Plemper et al, 2004(Plemper et al, , 2005Sun et al, 2006). Given the structural similarity of paramyxovirus F proteins, we tested some of these smallmolecule inhibitors and several derivatives in a NiV F proteinbased fusion assay (Niedermeier et al, 2009). Molecular modelling indicated that one compound fitted well into a cavity present in the NiV F protein.…”

Henipavirus pathogenesis and antiviral approaches

“…Furthermore, the use of a high throughput screening assay has recently allowed the identification of a broad-spectre, small antiviral molecule, capable of inhibiting cleavage of the glycoprotein of several highly pathogenic viruses in vitro, including NiV, HeV and Ebola virus [91]. In addition, other quinolone derivate specifically designed to fit into a cavity of the NiV F protein involved in the fusion process showed an important capacity of inhibiting syncytia formation [92]. Development of new strategies to screen viral entry inhibitors under BSL2 conditions, transposable to BSL3 and 4 associated pathogens [93] has recently opened novel perspectives for the more rapid identification of new antiviral components and identification of new compounds will certainly follow.…”

Microwave-assisted conversion of aromatic heterocyclic nitriles to various heterocyclic molecules

“…These types of heterocyclic compounds exhibit antitumor (8,9) anti-inflammatory (10,11), antibacterial (12), antiviral (13), and antimicrobial (14) activities. Since this investigation deals with a new approach to synthesize these medicinally important heterocyclic compounds, it is essential to review the procedures reported in literature.…”