Details

Autor(en) / Beteiligte

• Wang, Leah Liu
• Palermo, Nicholas
• Estrada, Leslie
• Thompson, Colton
• Patten, J.J.
• Anantpadma, Manu
• Davey, Robert A.
• Xiang, Shi-Hua

Titel

Identification of filovirus entry inhibitors targeting the endosomal receptor NPC1 binding site

Ist Teil von

• Antiviral research, 2021-05, Vol.189, p.105059-105059, Article 105059

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Filoviruses, mainly consisting of Ebola viruses (EBOV) and Marburg viruses (MARV), are enveloped negative-strand RNA viruses which can infect humans to cause severe hemorrhagic fevers and outbreaks with high mortality rates. The filovirus infection is mediated by the interaction of viral envelope glycoprotein (GP) and the human endosomal receptor Niemann-Pick C1 (NPC1). Blocking this interaction will prevent the infection. Therefore, we utilized an In silico screening approach to conduct virtual compound screening against the NPC1 receptor-binding site (RBS). Twenty-six top-hit compounds were purchased and evaluated by in vitro cell based inhibition assays against pseudotyped or replication-competent filoviruses. Two classes (A and U) of compounds were identified to have potent inhibitory activity against both Ebola and Marburg viruses. The IC50 values are in the lower level of micromolar concentrations. One compound (compd-A) was found to have a sub-micromolar IC50 value (0.86 μM) against pseudotyped Marburg virus. The cytotoxicity assay (MTT) indicates that compd-A has a moderate cytotoxicity level but the compd-U has much less toxicity and the CC50 value was about 100 μM. Structure-activity relationship (SAR) study has found some analogs of compd-A and -U have reduced the toxicity and enhanced the inhibitory activity. In conclusion, this work has identified several qualified lead-compounds for further drug development against filovirus infection. •In silico screening of 100K compounds against the receptor-binding site of Ebola virus.•Two classes of compounds were identified to have potent activities against filovirus entry from in vitro assays.•One compound was found to have a sub-micromolar IC50 (0.86 μM) against pseudotyped Marburg virus entry.•Molecular docking has deciphered the compound binding details including the interacting residues of the receptor.