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2,038 results on '"Tyrrell, D."'

207. A Virus From Epidemic Vomiting Disease

Author

Clarke, S. K. R., Cook, G. T., Egglestone, S. I., Hall, T. S., Miller, D. L., Reed, S. E., Rubenstein, D., Smith, A. J., and Tyrrell, D. A. J.

Published
1972

232. Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitorsElectronic supplementary information (ESI) available. See DOI: 10.1039/d1md00247c

Author

Bai, Bing, Arutyunova, Elena, Khan, Muhammad Bashir, Lu, Jimmy, Joyce, Michael A., Saffran, Holly A., Shields, Justin A., Kandadai, Appan Srinivas, Belovodskiy, Alexandr, Hena, Mostofa, Vuong, Wayne, Lamer, Tess, Young, Howard S., Vederas, John C., Tyrrell, D. Lorne, Lemieux, M. Joanne, and Nieman, James A.

Abstract

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitroSARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.

Published
2021
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237. Detailed Computational Study of the Active Site of the Hepatitis C Viral RNA Polymerase to Aid Novel Drug Design

Author

Barakat, Khaled H., Law, John, Prunotto, Alessio, Magee, Wendy C., Evans, David H., Tyrrell, D. Lorne, Tuszynski, Jack, and Houghton, Michael

Abstract

The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson–Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

Published
2024
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240. Highly bioavailable silibinin nanoparticles inhibit HCV infection

Author

Liu, Ching-Hsuan, primary, Lin, Chun-Ching, additional, Hsu, Wen-Chan, additional, Chung, Chueh-Yao, additional, Lin, Chih-Chan, additional, Jassey, Alagie, additional, Chang, Shun-Pang, additional, Tai, Chen-Jei, additional, Tai, Cheng-Jeng, additional, Shields, Justin, additional, Richardson, Christopher D, additional, Yen, Ming-Hong, additional, Tyrrell, D Lorne J, additional, and Lin, Liang-Tzung, additional

Published
2016
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243. Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate

Author

O'Shea, Daire, primary, Law, John, additional, Egli, Adrian, additional, Douglas, Donna, additional, Lund, Gary, additional, Forester, Sarah, additional, Lambert, Joshua, additional, Law, Mansun, additional, Burton, Dennis R., additional, Tyrrell, D. L. J., additional, Houghton, Michael, additional, Humar, Atul, additional, and Kneteman, Norman, additional

Published
2016
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246. Magnetic resonance imaging appearance of hypertensive encephalopathy in a dog

Author

Bowman, CA, Witham, A, Tyrrell, D, Long, SN, Bowman, CA, Witham, A, Tyrrell, D, and Long, SN

Abstract

A 16-year-old female spayed English Staffordshire terrier was presented for evaluation of a 10-month history of intermittent myoclonic episodes, and a one weeks history of short episodes of altered mentation, ataxia and collapse. Magnetic resonance imaging identified subcortical oedema, predominately in the parietal and temporal lobes and multiple cerebral microbleeds. Serum biochemistry, indirect blood pressure measurements and magnetic resonance imaging abnormalities were consistent with hypertensive encephalopathy secondary to chronic kidney disease.

Published
2015

247. Hepatitis C virus induced up-regulation of microRNA-27: a novel mechanism for hepatic steatosis

Author

Singaravelu, Ragunath, Chen, Ran, Lyn, Rodney K., Jones, Daniel M., O'Hara, Shifawn, Rouleau, Yanouchka, Cheng, Jenny, Srinivasan, Prashanth, Nasheri, Neda, Russell, Rodney S., Tyrrell, D. Lorne, and Pezacki, John Paul

Abstract

MicroRNAs (miRNAs) are small RNAs that posttranscriptionally regulate gene expression. Their aberrant expression is commonly linked with diseased states, including hepatitis C virus (HCV) infection. Herein, we demonstrate that HCV replication induces the expression of miR-27 in cell culture and in vivo HCV infectious models. Overexpression of the HCV proteins core and NS4B independently activates miR-27 expression. Furthermore, we establish that miR-27 overexpression in hepatocytes results in larger and more abundant lipid droplets, as observed by coherent anti-Stokes Raman scattering (CARS) microscopy. This hepatic lipid droplet accumulation coincides with miR-27b's repression of peroxisome proliferator-activated receptor (PPAR)-α and angiopoietin-like protein 3 (ANGPTL3), known regulators of triglyceride homeostasis. We further demonstrate that treatment with a PPAR-α agonist, bezafibrate, is able to reverse the miR-27b-induced lipid accumulation in Huh7 cells. This miR-27b-mediated repression of PPAR-α signaling represents a novel mechanism of HCV-induced hepatic steatosis. This link was further demonstrated in vivo through the correlation between miR-27b expression levels and hepatic lipid accumulation in HCV-infected SCID-beige/Alb-uPa mice. Conclusion: Collectively, our results highlight HCV's up-regulation of miR-27 expression as a novel mechanism contributing to the development of hepatic steatosis.

Published
2013
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