High-Content Screening to Identify Inhibitors of Dengue Virus Replication
Hoffstadt, J. G.; Wotring, J. W.; Porter, S.; Halligan, B. S.; O'Meara, M. J.; Tai, A. W.; Sexton, J. Z.
Show abstract
Dengue Virus (DENV) causes dengue fever, a pandemic-potential disease with currently no FDA-approved antivirals. Additionally, the available vaccine for DENV can increase the risk of severe dengue fever for those who have never had a DENV infection due to antibody-dependent enhancements. Thus, there is an urgent need to identify dengue virus antivirals. Antivirals that target NS4B, the replication compartment forming protein of DENV and the flavivirus family, are a promising new drug class that minimize cytotoxic effects to host cells. Drug-repurposing and high-content screening were leveraged to efficiently identify antivirals likely to inhibit NS4B. Using high-content screening, we quantified the morphological patterns of NS4B and envelope (E) protein expression versus time and developed a viral pseudotime model that was able to predict the infection progression to enable drug screening. We then developed a single cell infection classifier for antiviral efficacy and performed high-throughput drug screening of 960 compounds. We identified four concentration-dependent inhibitors of DENV with nanomolar potencies including: Nexium, Pralatrexate, GW4064, and LY411575. LY411575, a gamma secretase inhibitor, exhibited an IC50 of 72nM and reduced percent infection to levels indistinguishable from the mock infection control.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors 96%
- In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication 94%
- Methylene Blue has a potent antiviral activity against SARS-CoV-2 in the absence of UV-activation in vitro 94%
Similar papers in this journal
- Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells 95%
- Post-infection treatment with the E protein inhibitor BIT225 reduces disease severity and increases survival of k18-hACE2 transgenic mice infected with a lethal dose of SARS-CoV-2 94%
- A guanidine-based coronavirus replication inhibitor which targets the nsp15 endoribonuclease and selects for interferon-susceptible mutant viruses 94%
Similar papers in this journal
- Metal Coordinating Inhibitors of Rift Valley Fever virus Replication 95%
- Discovery of anti-SARS-CoV-2 S2 protein antibody CV804 with broad-spectrum reactivity with various beta coronaviruses and analysis of its pharmacological properties in vitro and in vivo 94%
- A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease. 93%
Similar papers in this journal
Similar papers in this journal
- Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture 95%
- Screening a library of FDA-approved and bioactive compounds for antiviral activity against SARS-CoV-2 95%
- The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.