A5040949737- Mosquito-borne diseases and control
- HIV Research and Treatment
- Viral Infections and Vectors
- Insect symbiosis and bacterial influences
- Malaria Research and Control
- Viral Infections and Outbreaks Research
- Bacteriophages and microbial interactions
- Herpesvirus Infections and Treatments
- Signaling Pathways in Disease
- Viral gastroenteritis research and epidemiology
- Insect Resistance and Genetics
- Respiratory viral infections research
- Protein Structure and Dynamics
- Vibrio bacteria research studies
- Animal Virus Infections Studies
- HIV/AIDS Research and Interventions
- Virology and Viral Diseases
- Hormonal Regulation and Hypertension
- Influenza Virus Research Studies
- Virus-based gene therapy research
- Dengue and Mosquito Control Research
- Enzyme Structure and Function
- Mycobacterium research and diagnosis
- Immune Cell Function and Interaction
- RNA and protein synthesis mechanisms
GlaxoSmithKline (United States)
2023
New York State Department of Health
2013-2018
Wadsworth Center
2013-2018
University at Albany, State University of New York
2017
State Farm (United States)
2016
University of Virginia
2006-2012
Influenza virus remains a global health threat, with millions of infections annually and the impending threat that strain avian influenza may develop into human pandemic. Despite its importance as pathogen, little is known about structure, in part because intrinsic structural variability (pleiomorphy): primary distinction between spherical elongated particles, but both vary size. Pleiomorphy has thwarted analysis by image reconstruction electron micrographs based on averaging many identical...
Cellular entry of Ebola virus (EBOV), a deadly hemorrhagic fever virus, is mediated by the viral glycoprotein (GP). The receptor-binding subunit GP must be cleaved (by endosomal cathepsins) in order for and infection to proceed. Cleavage appears proceed through 50-kDa 20-kDa intermediates, ultimately generating key 19-kDa core. How subsequently triggered bind membranes induce fusion remains mystery. Here we show that cannot liposomes response elevated temperature but can. Importantly, can at...
Entry of ebolavirus (EBOV) into cells is mediated by its glycoprotein (GP(1,2)), a class I fusion protein whose structure was recently determined (J. E. Lee et al., Nature 454:177-182, 2008). Here we confirmed two major predictions the structural analysis, namely, residues in GP(1) and GP(2) that remain after GP(1,2) proteolytically primed endosomal cathepsins for are critical binding to host cells. Mass spectroscopic analysis indicated contains 33 190 all GP(2). The location receptor site...
The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed NS2B cofactor of NS2B-NS3 heterocomplex protease displays conformational dynamic between active inactive states. Here, we developed switch assay based on split luciferase complementation (SLC) monitor change characterize candidate allosteric inhibitors. Binding...
In the Western Hemisphere, Zika virus is thought to be transmitted primarily by Aedes aegypti mosquitoes. To determine extent which Ae. albopictus mosquitoes from United States are capable of transmitting and influence dose, strain, mosquito species on vector competence, we evaluated multiple doses representative strains in Virus preparation (fresh vs. frozen) significantly affected infectivity We calculated 50% infectious 6.1-7.5 log 10 PFU/mL; minimum infective dose was 4.2 PFU/mL. were...
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here small molecule compounds, which putatively bind to SAM-binding site MTase inhibit its function, were identified by virtual screening. In vitro methylation experiments demonstrated significant inhibition 13 these with most potent compound displaying sub-micromolar inhibitory activity....
Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to SAM-binding site flavivirus MTase and inhibit its function. Six these computationally predicted binders were identified show significant inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against proteins other flaviviruses. Two also cytotoxicity high antiviral...
Retrovirus infection starts with the binding of envelope glycoproteins to host cell receptors. Subsequently, conformational changes in trigger fusion viral and cellular membranes. Some retroviruses, such as avian sarcoma/leukosis virus (ASLV), employ a two-step mechanism which receptor precedes low-pH activation fusion. We used cryo-electron tomography study virion/receptor/liposome complexes that simulate interactions ASLV virions cells. Binding soluble at neutral pH resulted capable...
The methyltransferase enzyme (MTase), which catalyzes the transfer of a methyl group from S-adenosyl-methionine (AdoMet) to viral RNA, and generates S-adenosyl-homocysteine (AdoHcy) as by-product, is essential for life cycle many significant human pathogen flaviviruses. Here we investigated inhibition flavivirus MTase by several AdoHcy-derivatives. Unexpectedly found that AdoHcy itself barely inhibits activities, even at high concentrations. was also shown not inhibit virus growth in...
Methylation of flavivirus RNA is vital for its stability and translation in the infected host cell. This methylation mediated by methyltransferase (MTase), which methylates N7 2'-O positions viral cap using S-adenosyl-l-methionine (SAM) as a methyl donor. In this report, we demonstrate that SAM, contrast to reaction by-product S-adenosyl-l-homocysteine, was assumed previously, copurified with Dengue (DNV) West Nile virus MTases produced Escherichia coli (E. coli). endogenous SAM can be...
Interchanging Leu-119 for Pro-119 at the tip of β4-β5 loop in first FK506 binding domain (FK1) FKBP51 and FKBP52 proteins, respectively, has been reported to largely reverse inhibitory (FKBP51) or stimulatory (FKBP52) effects these co-chaperones on transcriptional activity glucocorticoid androgen receptor-protein complexes. Previous NMR relaxation studies have identified exchange line broadening, indicative submillisecond conformational motion, throughout FK1 FKBP51, which are suppressed by...
The extensive set of NMR doublings exhibited by the immunophilin FKBP12 (FK506-binding protein 12) arose from a slow transition to cis-peptide configuration at Gly89 near tip 80's loop, site for numerous protein-recognition interactions both and other FKBP domain proteins. loop also linebroadening, indicative microsecond millisecond conformational dynamics, but only in trans-peptide state. G89A variant shifted trans-cis peptide equilibrium 88:12 33:67, whereas proline residue substitution...
We previously showed that the cysteines flanking internal fusion peptide of avian sarcoma/leukosis virus subtype A (ASLV-A) Env (EnvA) are important for infectivity and cell-cell fusion. Here we define stage at which required. The dispensable receptor-triggered membrane association but required lipid mixing step fusion, which, interestingly, displays a high pH onset biphasic profile. Second-site mutations partially restore infection mixing. These findings indicate EnvA (and perhaps by...
Dengue virus (DENV), an arthropod-borne ("arbovirus") virus, causes a range of human maladies ranging from self-limiting dengue fever to the life-threatening shock syndrome and proliferates well in two different taxa Animal Kingdom, mosquitoes primates. Mosquitoes primates show taxonomic group-specific intolerance certain codon pairs when expressing their genes by translation. This is called "codon pair bias". By necessity, viruses evolved delicately balance this fundamental difference open...
T cell responses to enteric bacteria are important in inflammatory bowel disease. I2, encoded by the pfiT gene of Pseudomonas fluorescens, is a T-cell superantigen associated with human Crohn's Here we report crystal structure at 1.7Å resolution and provide functional analysis interaction its homolog, PA2885, class II MHC. Both PA2885 bound mammalian cells stimulated proliferation lymphocytes. This binding was greatly inhibited anti-class MHC HLA-DR antibodies, lesser extent, anti HLA-DQ DP...
Abstract Dengue virus (DENV), an arthropod-borne (“arbovirus”) causing a range of human maladies ranging from self-limiting dengue fever to the life-threatening shock syndrome, proliferates well in two different taxa Animal Kingdom, mosquitoes and primates. Unexpectedly, primates have distinct preferences when expressing their genes by translation, e.g. members these show taxonomic group-specific intolerance certain codon pairs. This is called “codon pair bias”. By necessity, arboviruses...
Flaviviruses require the activity of their viral protease in order to process single polyprotein encoded by genome into individual proteins and assemble an infectious virion. This consists a large catalytic subunit (NS3) smaller accessory (NS2B) important for function. Using previously solved flavivirus crystal structures, we identified three putative sites interaction between NS2B NS3 which then queried with virtual screen NCI library compounds, followed subsequent vitro biochemical...