A5046015346- SARS-CoV-2 and COVID-19 Research
- PARP inhibition in cancer therapy
- interferon and immune responses
- Viral gastroenteritis research and epidemiology
- Animal Virus Infections Studies
- COVID-19 Clinical Research Studies
- Viral Infections and Immunology Research
- Electrostatic Discharge in Electronics
- Calcium signaling and nucleotide metabolism
- Computational Drug Discovery Methods
- RNA regulation and disease
- Virus-based gene therapy research
- RNA and protein synthesis mechanisms
- Advancements in Semiconductor Devices and Circuit Design
- Plant Virus Research Studies
- Hepatitis C virus research
- Herpesvirus Infections and Treatments
University of Kansas
2021-2025
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since its emergence in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, kinase R (PKR), oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV...
Significance Middle East respiratory syndrome coronavirus (MERS-CoV) causes highly lethal disease. MERS-CoV encodes innate immune antagonists, including accessory proteins NS4a and NS4b, unique to the merbeco lineage of betacoronaviruses, nsp15 protein endoribonuclease (EndoU), conserved among all coronaviruses. While mutation each antagonist alone has little effect on immunity, infections with recombinant MERS-CoVs mutations EndoU in combination either or NS4b activate signaling pathways...
Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies COVID-19. Included in these drug is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein a small domain at N terminus of nonstructural 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical both murine hepatitis virus (MHV) severe acute respiratory syndrome (SARS)-CoV virulence. However, potential target, it imperative understand how...
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied compound binding mode using X-ray crystallography, allowing us to design...
All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown important virus replication pathogenesis. Within Mac1, there are several regions highly across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how biochemical activities of these residues impact CoV replication, isoleucine...
ABSTRACT Neurotropic viruses are a major public health concern as they can cause encephalitis and other severe brain diseases. Many of these viruses, including flaviviruses, herpesviruses, rhabdoviruses alphaviruses enter the through olfactory neuroepithelium (ONE) in bulbs (OB). Due to low percentage that occurs following infections, it’s thought OBs have specialized innate immune responses eliminate viruses. Murine hepatitis virus strain JHM (JHMV) is model coronavirus causes mice access...
ABSTRACT ADP-ribosyltransferases (ARTs) mediate the transfer of ADP-ribose from NAD + to protein or nucleic acid substrates. This modification can be removed by several different types proteins, including macrodomains. Several ARTs, also known as PARPs, are stimulated interferon indicating ADP-ribosylation is an important aspect innate immune response. All coronaviruses (CoVs) encode for a highly conserved macrodomain (Mac1) that critical CoVs replicate and cause disease, effectively control...
ABSTRACT Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since emerging in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, kinase R (PKR), oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV...
ABSTRACT All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in non-structural protein 3. Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown important virus replication pathogenesis. Within Mac1, there are several regions highly across CoVs, including the glycine-isoleucine-phenylalanine motif. While we previously demonstrated importance of glycine residue CoV pathogenesis, impact isoleucine...
Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies COVID-19. Included in this set of is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical both murine hepatitis virus (MHV) severe acute respiratory syndrome (SARS)-CoV virulence. However, a potential drug target, it imperative understand how complete deletion impacts replication...
Abstract The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed to combat additional SARS-CoV-2 variants or novel CoVs. Here, we describe small molecule inhibitors for Mac1, which counters ADP-ribosylation mediated innate immune responses. compounds inhibiting Mac1 were discovered through high-throughput screening (HTS) using a protein FRET-based competition assay and...
We have demonstrated that aurora kinases play a role during HSV-1 lytic infection. Three kinase inhibitors significantly impaired immediate-early gene expression.
ABSTRACT Coronaviruses (CoVs) can emerge from zoonotic sources and cause severe diseases in humans animals. All CoVs encode for a macrodomain (Mac1) that binds to removes ADP-ribose target proteins. SARS-CoV-2 Mac1 promotes virus replication the presence of interferon (IFN) blocks production IFN, though mechanisms by which it mediates these functions remain unknown. inhibitors could help elucidate serve as therapeutic agents against CoV-induced diseases. We previously identified compound 4a...
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into humans in 2012, causing highly lethal disease. The severity of disease may be part because MERS-CoV is adept at antagonizing early innate immune pathways - interferon (IFN) production and signaling, protein kinase R (PKR), oligoadenylate synthetase ribonuclease L (OAS/RNase L) generated response to viral double-stranded (ds)RNA during genome replication. This contrast SARS-CoV-2, which we recently reported activates PKR...