A5012251433- RNA and protein synthesis mechanisms
- DNA and Nucleic Acid Chemistry
- Signaling Pathways in Disease
- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Hepatitis B Virus Studies
- Protein Structure and Dynamics
- Advanced NMR Techniques and Applications
- Bacterial Genetics and Biotechnology
- SARS-CoV-2 and COVID-19 Research
- Electron Spin Resonance Studies
- RNA modifications and cancer
- Bacteriophages and microbial interactions
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Cell Adhesion Molecules Research
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Structure and Function
- Spectroscopy and Quantum Chemical Studies
- Magnetism in coordination complexes
- Biochemical and Molecular Research
- HIV Research and Treatment
- Molecular spectroscopy and chirality
- Viral gastroenteritis research and epidemiology
- vaccines and immunoinformatics approaches
Gilead Sciences (United States)
2014-2025
Research Triangle Park Foundation
2012
TU Dortmund University
2003
University of California, San Francisco
1990-1999
GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitro and has demonstrated potent antiviral activity patients chronically infected with genotype 1 (GT1) HCV. exhibits reduced against GT2a (JFH1) subgenomic replicons (J6/JFH1) infectious virus, suggesting that the compound's mechanism action involves genotype-specific viral component. To further investigate action, we utilized susceptibility differences between GT1b by constructing series...
Cyclophilins are a family of peptidyl-prolyl isomerases that implicated in wide range diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity could serve as part all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle optimized using structure based design produce and bioavailable 3. The ring size...
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but generation potent, drug-like molecules through chemical synthesis challenging. In this study, set macrocyclic cyclophilin inhibitors was synthesized based on core structure natural product sanglifehrin A. Initial compound optimization identified valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in core, stereocenters at C14 C15, hydroxyl group m-tyrosine (m-Tyr) residue as key...
The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the genome and generate mRNA transcripts. While structures individual involved are known, how they assemble into a functioning superstructure not. Applying molecular modeling tools, including protein-protein docking, available nsp7-nsp16 nucleocapsid, we have constructed atomistic model these associate. Our principal finding hexameric, centered on nsp15. nsp15...
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This demonstrates potent in vitro inhibition replication (EC50 < 10 nM), direct binding purified NS4B protein (IC50 20 and an resistance pattern associated with (H94N/R, V105L/M, F98L) that are unique among reported clinical assets, suggestive the potential for additive or synergistic combination other small molecule inhibitors replication.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDeoxyribose conformation in [d(GTATATAC)]2: evaluation of sugar pucker by simulation double-quantum-filtered COSY cross-peaksUli Schmitz, Gerald Zon, and Thomas L. JamesCite this: Biochemistry 1990, 29, 9, 2357–2368Publication Date (Print):March 6, 1990Publication History Published online1 May 2002Published inissue 6 March 1990https://pubs.acs.org/doi/10.1021/bi00461a021https://doi.org/10.1021/bi00461a021research-articleACS PublicationsRequest...
Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients genotype 1 chronic infection. The mechanism action TGV has not been clearly defined despite the identification resistance mutations mapping to NS5B polymerase region. does inhibit enzymatic biochemical assays vitro, suggesting more complex cellular components. Here, we demonstrate that exerts anti-HCV utilizing unique chemical activation and subsequent direct...
A collaborative, open-science team undertook discovery of novel small molecule inhibitors the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase using a high throughput screening approach with potential to reveal new inhibition strategies. This screen yielded compound 5a, ligand possessing an electron-deficient double bond, as inhibitor nsp16 activity. Surprisingly, X-ray crystal structures revealed that 5a covalently binds within previously unrecognized cryptic pocket near S-adenosylmethionine...
A new series of short pyrrole tetraamides are described whose submicromolar DNA binding affinity is an essential component for their strong antibacterial activity. This class compounds related to the linked bis-netropsins and bis-distamycins, but here, only one amino-pyrrole-carboxamide unit amidine tail connected either side a central dicarboxylic acid linker. The highest degree binding, measured by compound-induced changes in UV melting temperatures AT-rich oligomer, was observed flat,...
Elucidation of the mechanism action HCV NS5B polymerase thumb site II inhibitors has presented a challenge. Current opinion holds that these allosteric stabilize closed, inactive enzyme conformation, but how this inhibition is accomplished mechanistically not well understood. Here, using panel proteins with mutations in key regulatory motifs NS5B--the C-terminal tail and β-loop--in conjunction diverse set inhibitors, we show possess distinct action. A combination activity studies direct...
A tremendous research and development effort was exerted toward combating chronic hepatitis C, ultimately leading to curative oral treatments, all of which are targeting viral proteins. Despite the advantage numerous targets allowing for broad C virus (HCV) genotype coverage, only host target inhibitors that advanced into clinical were Cyclosporin based cyclophilin inhibitors. While cyclosporin-based molecules typically require a fermentation process, Gilead successfully pursued fully...
Chronic hepatitis B (CHB) is a global health care challenge and major cause of liver disease. To find new therapeutic avenues with potential to functionally cure chronic Hepatitis virus (HBV) infection, we performed focused screen epigenetic modifiers identify inhibitors replication or gene expression. From this work identified isonicotinic acid the histone lysine demethylase 5 (KDM5) potent anti-HBV activity. enhance cellular permeability accumulation most KDM5 inhibitor (GS-080) an ester...
Despite suppressive antiretroviral therapy (ART), HIV-1 persists in latent reservoirs that seed new HIV infections if ART is interrupted, necessitating lifelong for people with HIV. Activation of during could improve recognition and elimination infected cells by the immune system. Protein kinase C (PKC) isozymes increase transcription hence are potential latency reversal agents. However, clinical utility PKCs this application limited due to toxicity, which poorly understood. Our studies...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDynamic interpretation of NMR data: molecular dynamics with weighted time-averaged restraints and ensemble R-factorUli Schmitz, Anil Kumar, Thomas L. JamesCite this: J. Am. Chem. Soc. 1992, 114, 26, 10654–10656Publication Date (Print):December 1, 1992Publication History Published online1 May 2002Published inissue 1 December 1992https://pubs.acs.org/doi/10.1021/ja00052a082https://doi.org/10.1021/ja00052a082research-articleACS PublicationsRequest...
The signal recognition particle (SRP) is a phylogenetically conserved ribonucleoprotein required for cotranslational targeting of proteins to the membrane endoplasmic reticulum bacterial plasma membrane. Domain IV SRP RNA consists short stem-loop structure with two internal loops that contain most nucleotides molecule. All known essential interactions occur in moiety containing domain IV. solution 43-nt comprising complete Escherichia coli was determined by multidimensional NMR and...