6 research outputs found
Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing Ebola virus immune evasion
Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication
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MMWR. Morbidity and mortality weekly report
Malaria in Refugees from Tanzania--King County, Washington, 2007 -- Syphilis Testing Algorithms Using Treponemal Tests for Initial Screening--Four Laboratories, New York City, 2005-2006 -- Infection Control Requirements for Dialysis Facilities and Clarification Regarding Guidance on Parenteral Medication Vials -- Notice to Readers: Preventive Medicine Residency Application Deadline--October 1, 2008 -- Erratum: Vol. 57, No. SS-6 -- QuickStats: Age-Adjusted Death Rates by Race and Sex--United States, 2006 -- Notifiable Diseases/Deaths in Selected Cities Weekly Information.2008627
Broad Spectrum Inhibitor of Influenza A and B Viruses Targeting the Viral Nucleoprotein
S119 was a top hit from an ultrahigh
throughput screen performed to identify novel inhibitors of influenza
virus replication. It showed a potent antiviral effect (50% inhibitory
concentration, IC<sub>50</sub> = 20 nM) and no detectable cytotoxicity
(50% cytotoxic concentration, CC<sub>50</sub> > 500 μM) to
yield a selectivity index greater than 25 000. Upon investigation,
we found that S119 selected for resistant viruses carrying mutations
in the viral nucleoprotein (NP). These resistance mutations highlight
a likely S119 binding site overlapping with but not identical to that
found for the compound nucleozin. Mechanism of action studies revealed
that S119 affects both the oligomerization state and cellular localization
of the NP protein which has an impact on viral transcription, replication,
and protein expression. Through a hit-to-lead structure–activity
relationship (SAR) study, we found an analog of S119, named S119-8,
which had increased breadth of inhibition against influenza A and
B viruses accompanied by only a small loss in potency. Finally, <i>in vitro</i> viral inhibition assays showed a synergistic relationship
between S119-8 and oseltamivir when they were combined, indicating
the potential for future drug cocktails
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Structure-Based Discovery of Inhibitors of the SARS-CoV‑2 Nsp14 N7-Methyltransferase
An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme's SAM site, leading to three inhibitors with IC50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization
Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors
The
Ebola virus (EBOV) causes severe human infection that lacks
effective treatment. A recent screen identified a series of compounds
that block EBOV-like particle entry into human cells. Using data from
this screen, quantitative structure–activity relationship models
were built and employed for virtual screening of a ∼17 million
compound library. Experimental testing of 102 hits yielded 14 compounds
with IC<sub>50</sub> values under 10 μM, including several sub-micromolar
inhibitors, and more than 10-fold selectivity against host cytotoxicity.
These confirmed hits include FDA-approved drugs and clinical candidates
with non-antiviral indications, as well as compounds with novel scaffolds
and no previously known bioactivity. Five selected hits inhibited
BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine
(0.34 μM). Additional studies of these novel anti-EBOV compounds
revealed their mechanisms of action, including the inhibition of NPC1
protein, cathepsin B/L, and lysosomal function. Compounds identified
in this study are among the most potent and well-characterized anti-EBOV
inhibitors reported to date
Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors
The
Ebola virus (EBOV) causes severe human infection that lacks
effective treatment. A recent screen identified a series of compounds
that block EBOV-like particle entry into human cells. Using data from
this screen, quantitative structure–activity relationship models
were built and employed for virtual screening of a ∼17 million
compound library. Experimental testing of 102 hits yielded 14 compounds
with IC<sub>50</sub> values under 10 μM, including several sub-micromolar
inhibitors, and more than 10-fold selectivity against host cytotoxicity.
These confirmed hits include FDA-approved drugs and clinical candidates
with non-antiviral indications, as well as compounds with novel scaffolds
and no previously known bioactivity. Five selected hits inhibited
BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine
(0.34 μM). Additional studies of these novel anti-EBOV compounds
revealed their mechanisms of action, including the inhibition of NPC1
protein, cathepsin B/L, and lysosomal function. Compounds identified
in this study are among the most potent and well-characterized anti-EBOV
inhibitors reported to date