A5029022788- Viral gastroenteritis research and epidemiology
- Animal Virus Infections Studies
- Viral Infections and Immunology Research
- SARS-CoV-2 and COVID-19 Research
- Virus-based gene therapy research
- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- Respiratory viral infections research
- Synthesis and biological activity
- Advanced Thermodynamic Systems and Engines
- Hepatitis Viruses Studies and Epidemiology
- Influenza Virus Research Studies
- COVID-19 Clinical Research Studies
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Clostridium difficile and Clostridium perfringens research
- Bacteriophages and microbial interactions
- Chemical Synthesis and Analysis
- Viral Infectious Diseases and Gene Expression in Insects
- Chemical Reactions and Isotopes
- Vector-Borne Animal Diseases
- Protein Structure and Dynamics
- Veterinary medicine and infectious diseases
- Hepatitis C virus research
- SARS-CoV-2 detection and testing
Kansas State University
2015-2024
National Institute of Allergy and Infectious Diseases
2004-2013
National Institutes of Health
2004-2013
Wichita State University
2012
The Ohio State University
1995-2005
Universidade Federal de Goiás
2004
University of Minnesota
1983
Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine 1 (MNV-1) infects macrophage-like cells in vivo and replicates primary dendritic macrophages. MNV-1 growth was inhibited by interferon-αβ receptor STAT-1, associated with extensive rearrangements of intracellular membranes. An amino acid substitution capsid protein serially passaged virulence attenuation vivo. This is first report replication a cell...
Optimized small-molecule 3C-like protease inhibitors show potency against human coronaviruses in both cell culture and a mouse model.
Coronaviruses infect animals and humans causing a wide range of diseases. The diversity coronaviruses in many mammalian species is contributed by relatively high mutation recombination rates during replication. This dynamic nature may facilitate cross-species transmission shifts tissue or cell tropism host, resulting substantial change virulence. Feline enteric coronavirus (FECV) causes inapparent mild enteritis cats, but highly fatal disease, called feline infectious peritonitis (FIP), can...
Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is great importance. We show that mild inhibition mitochondrial complex I with small molecule CP2 reduces levels amyloid beta and phospho-Tau averts cognitive decline in three animal models familial AD. Low-mass molecular dynamics simulations biochemical studies confirmed competes flavin mononucleotide for binding the redox center leading elevated AMP/ATP ratio activation AMP-activated protein kinase neurons mouse...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is virus encoded by SARS-CoV-2, which essential for replication. We have previously reported series of small-molecule 3CLpro inhibitors effective inhibiting replication human coronaviruses including SARS-CoV-2 in cell culture and animal models. Here we generated deuterated variants inhibitor, GC376, evaluated the antiviral effect against...
A series of nondeuterated and deuterated dipeptidyl aldehyde masked inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease biochemical cell-based assays. Several the were also be nanomolar Middle East coronavirus protease. The corresponding latent bisulfite adducts equipotent precursor aldehydes. High-resolution cocrystal structures confirmed...
A porcine enteric calicivirus (PEC), strain Cowden in the family Caliciviridae (genus Sapovirus ), can be propagated a continuous cell line, LLC-PK cells, but only presence of an intestinal content fluid filtrate from gnotobiotic pigs. This culture system is presently vitro model among caliciviruses that cause gastrointestinal disease, including members genera and Norovirus . We report here identification bile acids as active factors essential for PEC growth. Bile allowed growth induced...
The development of effective therapies for noroviral gastroenteritis has been hampered by the absence a cell culture system. Recently, we reported generation Norwalk virus (NV) replicon-bearing cells in BHK21 and Huh-7 demonstrated that alpha interferon (IFN-alpha) effectively inhibited replication NV these cells. In continuing studies screening potential antinoroviral agents, tested IFN-gamma ribavirin their effects on Like IFN-alpha, cells, showing reduction genome proteins dose-dependent...
ABSTRACT The third open reading frame (ORF3) located at the 3′ end of genomic RNA feline calicivirus (FCV) encodes a small (12.2-kDa) minor structural protein 106 amino acids designated VP2. Point mutations and deletions were introduced into an infectious FCV cDNA clone in order to evaluate functional importance ORF3 its encoded protein, Deletion entire sequence was lethal for virus, evidence found strong selective pressure produce VP2 protein. Extended 5′ ORF3, as well introduction stop...
Caliciviruses are single-stranded RNA viruses that cause a wide range of diseases in both humans and animals, but little is known about the regulation cellular translation during infection. We used two distinct calicivirus strains, MD145-12 (genus Norovirus) feline (FCV) Vesivirus), to investigate potential strategies by caliciviruses inhibit translation. Recombinant 3C-like proteinases (r3CL(pro)) from norovirus FCV were found cleave poly(A)-binding protein (PABP) absence other viral...
SUMMARY Intestines from 48 swine with enteric disease were examined by bacteriologic cultural technique for the presence of various Campylobacter species. Histopathologic techniques used to determine whether submitted specimens had lesions either proliferative ileitis or other diseases. Three species identified as jejuni/coli , sputorum ss mucosalis and hyointestinalis (proposed new species) on basis biochemical characteristics response inhibitory substances. The C was isolated 18 27 (67%)...
Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including responses to viral infection. As obligate intracellular pathogens, viruses have the capacity manipulate ubiquitin cycle their advantage by encoding Ub-modifying proteins deubiquitinases (DUBs). However, how DUBs modulate specific infections, such as norovirus, poorly understood. To examine role of during norovirus infection, we used WP1130, small molecule inhibitor subset DUBs. Replication murine...
Feline infectious peritonitis and virulent, systemic calicivirus infection are caused by certain types of feline coronaviruses (FCoVs) caliciviruses (FCVs), respectively, important diseases with high fatality rates in members the Felidae family. While FCoV FCV belong to two distinct virus families, Coronaviridae Caliciviridae, they share a dependence on viral 3C-like protease (3CLpro) for their replication. Since 3CLpro is functionally structurally conserved among these viruses essential...
There is mounting evidence of SARS-CoV-2 spillover from humans into many domestic, companion, and wild animal species. Research indicates that have infected white-tailed deer, deer-to-deer transmission has occurred, indicating deer could be a wildlife reservoir source novel variants. We examined the hypothesis Omicron variant actively asymptomatically infecting free-ranging New York City. Between December 2021 February 2022, 155 on Staten Island, York, were anesthetized for gross...
The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative discovery and development direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) emerged as a validated target for therapeutics because pivotal role it plays in replication. We describe herein structure-guided design highly potent inhibitors 3CLpro that incorporate their structure novel spirocyclic elements optimizing potency by accessing new...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoonotic agent capable of infecting humans and wide range animal species. Over the duration pandemic, mutations in SARS-CoV-2 spike (S) protein have arisen, culminating spread several variants concern (VOCs) with various degrees altered virulence, transmissibility, neutralizing antibody escape. In this study, we used pseudoviruses that express specific S substitutions cell lines angiotensin-converting enzyme (ACE2) from nine...
ABSTRACT Porcine enteric calicivirus (PEC) is associated with diarrhea in pigs, and to date it the only cultivable (tissue culture-adapted [TC] PEC/Cowden). Based on sequence analysis of cDNA clones reverse transcription-PCR products, TC PEC/Cowden has an RNA genome 7,320 bp, excluding its 3′ poly(A) + tail. The organized two open reading frames (ORFs), similar organizations human Sapporo-like viruses (SLVs) lagoviruses. ORF1 encodes polyprotein that fused contiguous capsid protein. ORF2 at...
Norwalk virus (NV) is a prototype strain of the noroviruses (family Caliciviridae) that have emerged as major causes acute gastroenteritis worldwide. I developed NV replicon systems using reporter proteins such neomycin-resistant protein (NV replicon-bearing cells) and green fluorescent (pNV-GFP) demonstrated these were excellent tools to study replication in cell culture. In present study, first performed DNA microarray analysis cells identify cellular factors associated with replication....
The lack of an animal model for human norovirus (HuNoV) has hindered the development therapeutic strategies. This study demonstrated that a commonly used cholesterol-lowering statin medication, simvastatin, which increases HuNoV replication in vitro replicon system, also enhances infectivity gnotobiotic (Gn) pig model. In contrast, oral treatment with interferon (IFN)-α reduces infectivity. Young piglets, all A or H1 histo-blood group antigens on enterocytes, were treated orally 8 mg/kg/day...