首页|Identification of filovirus entry inhibitors targeting the endosomal receptor NPC1 binding site
Identification of filovirus entry inhibitors targeting the endosomal receptor NPC1 binding site
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NSTL
Elsevier
Filoviruses, mainly consisting of Ebola viruses (EBOV) and Marburg viruses (MARV), are enveloped negativestrand 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 mu M) against pseudotyped Marburg virus. The cytotoxicity assay (MTT) indicates that compdA has a moderate cytotoxicity level but the compd-U has much less toxicity and the CC50 value was about 100 mu M. 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 leadcompounds for further drug development against filovirus infection.
In silico screeningFilovirusEntry inhibitorsNiemann-pick C1 (NPC1)Envelope glycoprotein (GP)Receptor binding site (RBS)
Wang, Leah Liu、Palermo, Nicholas、Estrada, Leslie、Thompson, Colton、Patten, J. J.、Anantpadma, Manu、Davey, Robert A.、Xiang, Shi-Hua
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Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA
Univ Nebraska Med Ctr, VCR Cores, Computat Chem Core Facil, Omaha, NE 68198 USA
Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE 68583 USA
Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA
NSTL
Elsevier
