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Published on: March 1, 2019
Identification of filovirus entry inhibitors targeting the endosomal receptor NPC1 binding site
Leah Liu Wang1, Nicholas Palermo2, Leslie Estrada3
1School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
Abstract:
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.
Insights
Researchers screened compounds to block filovirus (Ebola and Marburg virus) infection by targeting the NPC1 receptor. Two compound classes showed potent activity, with one lead compound demonstrating sub-micromolar efficacy against Marburg virus.
Area of Science:
- Virology
- Drug Discovery
- Computational Chemistry
Background:
- Filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fevers with high mortality.
- Viral entry into human cells is mediated by the interaction between the filovirus glycoprotein (GP) and the Niemann-Pick C1 (NPC1) receptor.
Purpose of the Study:
- To identify novel compounds that inhibit filovirus entry by targeting the NPC1 receptor-binding site.
- To evaluate the efficacy and safety of identified compounds against filovirus infections.
Main Methods:
- In silico virtual screening of compounds against the NPC1 receptor-binding site.
- In vitro cell-based inhibition assays using pseudotyped and replication-competent filoviruses.
- Cytotoxicity assays (MTT) and structure-activity relationship (SAR) studies.
Main Results:
- Two classes of compounds (A and U) exhibited potent inhibitory activity against both EBOV and MARV.
- One compound (compd-A) showed sub-micromolar IC50 (0.86 μM) against pseudotyped Marburg virus.
- Compound compd-U demonstrated significantly lower toxicity (CC50 ≈ 100 μM) compared to compd-A, with SAR studies revealing analogs with improved activity and reduced toxicity.
Conclusions:
- The study identified promising lead compounds for developing new therapeutics against filovirus infections.
- Targeting the NPC1-GP interaction is a viable strategy for filovirus antiviral drug development.
- Further optimization of lead compounds is warranted to enhance efficacy and minimize toxicity.
