21 results on '"Justin Shields"'
Search Results
2. Author Correction: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
- Author
-
Wayne Vuong, Muhammad Bashir Khan, Conrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, Ryan T. McKay, Marco J. van Belkum, Michael A. Joyce, Howard S. Young, D. Lorne Tyrrell, John C. Vederas, and M. Joanne Lemieux
- Subjects
Science - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
- Full Text
- View/download PDF
3. Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication.
- Author
-
Christopher J Neufeldt, Michael A Joyce, Aviad Levin, Rineke H Steenbergen, Daniel Pang, Justin Shields, D Lorne J Tyrrell, and Richard W Wozniak
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Hepatitis C virus (HCV) infection induces formation of a membranous web structure in the host cell cytoplasm where the viral genome replicates and virions assemble. The membranous web is thought to concentrate viral components and hide viral RNA from pattern recognition receptors. We have uncovered a role for nuclear pore complex proteins (Nups) and nuclear transport factors (NTFs) in the membranous web. We show that HCV infection leads to increased levels of cytoplasmic Nups that accumulate at sites enriched for HCV proteins. Moreover, we detected interactions between specific HCV proteins and both Nups and NTFs. We hypothesize that cytoplasmically positioned Nups facilitate formation of the membranous web and contribute to the compartmentalization of viral replication. Accordingly, we show that transport cargo proteins normally targeted to the nucleus are capable of entering regions of the membranous web, and that depletion of specific Nups or Kaps inhibits HCV replication and assembly.
- Published
- 2013
- Full Text
- View/download PDF
4. SARS-COV-2 recombinant Receptor-Binding-Domain (RBD) induces neutralizing antibodies against variant strains of SARS-CoV-2 and SARS-CoV-1
- Author
-
Kanti Pabbaraju, Matthew A. Croxen, Holly A. Saffran, Kevin Crawford, Michael Logan, Gerald LaChance, Darren Hockman, John Lok Man Law, D. Lorne Tyrrell, Abdolamir Landi, Janelle Johnson, Graham Tipples, Raelynn Brassard, Justin Shields, Eve Hobart, Michael Houghton, M. Joanne Lemieux, Michael A. Joyce, and Elena Arutyunova
- Subjects
COVID19 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Booster dose ,Biology ,Antibodies, Viral ,Article ,Neutralization ,RBD ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,law ,Humans ,Variant ,Antibody ,030304 developmental biology ,0303 health sciences ,General Veterinary ,General Immunology and Microbiology ,SARS-CoV-2 ,VOC ,Public Health, Environmental and Occupational Health ,COVID-19 ,Antibodies, Neutralizing ,Virology ,In vitro ,3. Good health ,Titer ,Infectious Diseases ,Spike Glycoprotein, Coronavirus ,Recombinant DNA ,biology.protein ,Molecular Medicine ,Vaccine ,030217 neurology & neurosurgery - Abstract
SARS-CoV-2 is the etiological agent of COVID19. There are currently several licensed vaccines approved for human use and most of them are targeting the spike protein (or virion) in the virion envelope to induce protective immunity. Recently, variants that spread more quickly have emerged. There is evidence that some of these variants are less sensitive to neutralization in vitro, but it is not clear whether they can evade vaccine induced protection. In this study, we tested the utility of SARS-CoV-2 spike RBD as a vaccine antigen and explore the effect of formulation with Alum/MPLA or AddaS03 adjuvants. Our results indicate RBD induces high titers of neutralizing antibodies and activates strong cellular immune responses. There is also significant cross-neutralisation of variants B1.1.7 and B.1.351 and to a lesser extent, SARS-CoV-1. These results indicate that recombinant RBD can be a viable candidate as a stand-alone vaccine or as a booster shot to diversify our strategy for COVID19 protection.
- Published
- 2021
5. Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability
- Author
-
Muhammad Bashir Khan, Jimmy Lu, Elena Arutyunova, John C. Vederas, James A. Nieman, Howard S. Young, Mohammad Rahim, Yanhua Du, Wayne Vuong, M. Joanne Lemieux, Marco J. van Belkum, Holly A. Saffran, Conrad Fischer, Bing Bai, Alexandr Belovodskiy, Michael A. Joyce, Fusen Lin, Jia Xu, Hena Mostafa, Justin Shields, Darren Hockman, Tess Lamer, D. Lorne Tyrrell, Appan Srinivas Kandadai, Sardeev K Bajwa, and Zhengxian Gu
- Subjects
0303 health sciences ,Protease ,010405 organic chemistry ,Peptidomimetic ,viruses ,medicine.medical_treatment ,medicine.disease_cause ,01 natural sciences ,In vitro ,3. Good health ,0104 chemical sciences ,Glutamine ,03 medical and health sciences ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Viral replication ,Drug Discovery ,medicine ,Lactam ,Molecular Medicine ,Cytotoxicity ,030304 developmental biology ,Coronavirus - Abstract
Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.
- Published
- 2021
6. Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2
- Author
-
Shima Shahbaz, Mohammad Osman, Lai Xu, Olaide Oyegbami, D. Lorne Tyrrell, Shokrollah Elahi, Wendy I Sligl, Justin Shields, and Michael A. Joyce
- Subjects
Male ,0301 basic medicine ,T-Lymphocytes ,Adaptive Immunity ,Biochemistry ,Hemoglobins ,Mice ,0302 clinical medicine ,Erythropoiesis ,skin and connective tissue diseases ,Aged, 80 and over ,Erythroid Precursor Cells ,Infectivity ,B-Lymphocytes ,Mice, Inbred BALB C ,0303 health sciences ,Erythroid precursors/progenitors ,Serine Endopeptidases ,Middle Aged ,Acquired immune system ,3. Good health ,Cell biology ,RBCs ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,CD71+ erythroid cells ,Female ,Angiotensin-Converting Enzyme 2 ,medicine.symptom ,medicine.drug ,Adult ,Adolescent ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,dexamethasone ,Transferrin receptor ,Biology ,TMPRSS2 ,Article ,Young Adult ,03 medical and health sciences ,Genetics ,medicine ,Animals ,Humans ,Lymphocyte Count ,Progenitor cell ,Dexamethasone ,B cell ,Aged ,030304 developmental biology ,SARS-CoV-2 ,fungi ,COVID-19 ,Cell Biology ,Hypoxia (medical) ,Oxygen ,030104 developmental biology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
SARS-CoV-2 infection is associated with lower blood oxygen levels, even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here, we show significantly enriched CD71+ erythroid precursors/progenitors in the blood circulation of COVID-19 patients. We found that these cells have distinctive immunosuppressive properties. In agreement, we observed a strong negative correlation between the frequency of these cells with T and B cell proportions in COVID-19 patients. The expansion of these CD71+ erythroid precursors/progenitors was negatively correlated with the hemoglobin levels. A subpopulation of abundant erythroid cells, CD45+ CD71+ cells, co-express ACE2, TMPRSS2, CD147, and CD26, and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. This provides a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients., In this article Elahi and colleagues show that COVID-19 infection is associated with significant expansion of erythroid precursors/progenitors in the blood of patients. These cells suppress patients' immune response against SARS-CoV-2 infection. Also, they express ACE2 and TMPRSS2 and get infected with SARS-CoV-2. In turn, pre-treatment with dexamethasone significantly diminishes ACE2/TMPRSS2 expression and subsequently reduces their infectivity with SARS-CoV-2.
- Published
- 2021
7. Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors
- Author
-
Howard S. Young, Muhammad Bashir Khan, Hena Mostafa, Tess Lamer, Alexandr Belovodskiy, Justin Shields, Wayne Vuong, Holly A. Saffran, Michael A. Joyce, Elena Arutyunova, Jimmy Lu, James A. Nieman, D. Lorne Tyrrell, Appan Srinivas Kandadai, Bing Bai, John C. Vederas, and M. Joanne Lemieux
- Subjects
Nitrile ,Stereochemistry ,Peptidomimetic ,medicine.medical_treatment ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Protease inhibitor (pharmacology) ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Protease ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,In vitro ,3. Good health ,0104 chemical sciences ,Drug development ,Viral replication ,Molecular Medicine ,Efflux - 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 vitro SARS-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
8. Author Correction: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
- Author
-
D. Lorne Tyrrell, John C. Vederas, Michael A. Joyce, Howard S. Young, Wayne Vuong, Tess Lamer, Holly A. Saffran, Marco J. van Belkum, Elena Arutyunova, Muhammad Bashir Khan, Ryan T. McKay, M. Joanne Lemieux, Justin Shields, and Conrad Fischer
- Subjects
Feline coronavirus ,Pyrrolidines ,medicine.medical_treatment ,General Physics and Astronomy ,Viral Nonstructural Proteins ,medicine.disease_cause ,Crystallography, X-Ray ,Virus Replication ,Cytopathogenic Effect, Viral ,Chlorocebus aethiops ,Prodrugs ,lcsh:Science ,Coronavirus 3C Proteases ,media_common ,Multidisciplinary ,Molecular Structure ,Proteases ,Cysteine Endopeptidases ,Severe acute respiratory syndrome-related coronavirus ,Drug ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Science ,media_common.quotation_subject ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biology ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Betacoronavirus ,Inhibitory Concentration 50 ,Target identification ,medicine ,Animals ,Humans ,Protease Inhibitors ,Coronavirus, Feline ,Author Correction ,Vero Cells ,X-ray crystallography ,Protease ,Binding Sites ,SARS-CoV-2 ,Drug Repositioning ,General Chemistry ,Virology ,Viral replication ,A549 Cells ,lcsh:Q ,Sulfonic Acids - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
9. Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
- Author
-
D. Lorne Tyrrell, Ryan T. McKay, M. Joanne Lemieux, Wayne Vuong, John C. Vederas, Elena Arutyunova, Marco J. van Belkum, Muhammad Bashir Khan, Michael A. Joyce, Holly A. Saffran, Conrad Fischer, Justin Shields, Howard S. Young, and Tess Lamer
- Subjects
Drug ,0301 basic medicine ,Feline coronavirus ,Proteases ,media_common.quotation_subject ,medicine.medical_treatment ,Science ,viruses ,General Physics and Astronomy ,medicine.disease_cause ,01 natural sciences ,Virus ,General Biochemistry, Genetics and Molecular Biology ,Article ,chemistry.chemical_compound ,03 medical and health sciences ,0302 clinical medicine ,Target identification ,medicine ,lcsh:Science ,skin and connective tissue diseases ,030304 developmental biology ,media_common ,Coronavirus ,X-ray crystallography ,0303 health sciences ,Multidisciplinary ,Protease ,010405 organic chemistry ,Chemistry ,SARS-CoV-2 ,fungi ,Hemithioacetal ,virus diseases ,General Chemistry ,Prodrug ,Virology ,Feline infectious peritonitis ,0104 chemical sciences ,3. Good health ,body regions ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,lcsh:Q - Abstract
The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19., Coronavirus main protease is essential for viral polyprotein processing and replication. Here Vuong et al. report efficient inhibition of SARS-CoV-2 replication by the dipeptide-based protease inhibitor GC376 and its parent GC373, which were originally used to treat feline coronavirus infection.
- Published
- 2020
10. Comprehensive in vitro characterization of PD-L1 small molecule inhibitors
- Author
-
Lai Xu, Michael Smylie, Mary M. Hitt, James A. Nieman, John Walker, Guangzhi Zhang, Joydeb Kumar Kundu, Isobel Okoye, Seyedeh Nargess Hosseini, Nutan Srivastava, William L. Turnbull, Hena Mostafa, Dinesh Babu, Khaled Barakat, Justin Shields, Katharine Cheryl Agopsowicz, Frederick G. West, Tae Chul Moon, D. Lorne Tyrrell, Yasser M Tabana, Appan Srinivas Kandadai, Alexandr Belovodskiy, Marawan Ahmed, Shokrollah Elahi, Aravindhan Ganesan, Elena Arutyunova, Michael Houghton, Arno G. Siraki, and M. Joanne Lemieux
- Subjects
0301 basic medicine ,Cancer therapy ,Cell Survival ,Peptidomimetic ,medicine.medical_treatment ,Cell ,lcsh:Medicine ,Molecular Dynamics Simulation ,Jurkat cells ,B7-H1 Antigen ,Article ,Small Molecule Libraries ,Jurkat Cells ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Genes, Reporter ,PD-L1 ,medicine ,Humans ,lcsh:Science ,Cytotoxicity ,Immunoassay ,Binding Sites ,Multidisciplinary ,biology ,Chemistry ,lcsh:R ,Antibodies, Monoclonal ,Small molecule ,In vitro ,Protein Structure, Tertiary ,030104 developmental biology ,medicine.anatomical_structure ,Leukocytes, Mononuclear ,Cancer research ,biology.protein ,Interleukin-2 ,lcsh:Q ,Peptidomimetics ,Immunotherapy ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors.
- Published
- 2019
11. Structural insights into the feline coronavirus drug GC376, which inhibits the main protease of SARS-CoV-2 and blocks virus replication
- Author
-
Elena Arutyunova, Muhammad Bashir Khan, Joanne Lemieux, D. Lorne Tyrrell, Justin Shields, Howard S. Young, John C. Vederas, Wayne Vuong, Michael A. Joyce, Holly A. Saffran, Conrad Fischer, Ryan T. McKay, Marco J. van Belkum, and Tess Lamer
- Subjects
Drug ,Feline coronavirus ,Protease ,medicine.medical_treatment ,media_common.quotation_subject ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biology ,Condensed Matter Physics ,medicine.disease_cause ,Biochemistry ,Virology ,Inorganic Chemistry ,Viral replication ,Structural Biology ,medicine ,General Materials Science ,Physical and Theoretical Chemistry ,media_common - Published
- 2020
12. Smart Machines and Smarter Policy: Foreign Investment Regulation, National Security, and Technology Transfer in the Age of Artificial Intelligence
- Author
-
Justin Shields
- Subjects
Government ,National security ,Procurement ,business.industry ,Foreign direct investment ,Artificial intelligence ,Foreign national ,Venture capital ,business ,Investment (macroeconomics) ,China - Abstract
The Foreign Risk Review Modernization Act, a bill introduced to Congress in 2017 that seeks to strengthen the Committee on Foreign Investment in the United States (CFIUS), has the potential to increase restrictions on Chinese companies investing in the U.S. artificial intelligence (AI) industry. Although the bill addresses legitimate national security concerns related to the military applications of AI, it also has the potential to negatively impact the U.S. AI industry and the U.S. economy as a whole. Currently, the combination of a Chinese government focused on strategic technology acquisitions, the open and diffuse nature of AI systems, the off-the-shelf nature of defense technology procurement, the integrated Chinese and U.S. AI industries, and the connection of Chinese tech companies to the Chinese Communist Party create a pipeline for technology transfer from U.S. companies to Chinese government entities. Given the vague nature of what constitutes a national security threat according to CFIUS, past high profile CFIUS action against Chinese companies investing in the U.S. technology sector and an emerging bipartisan consensus that CFIUS needs to be strengthened, there is a strong potential for new foreign investment restrictions. Restricting Chinese investment in the U.S. AI industry, however, may be counterproductive, because it may negatively impact U.S. economic competitiveness by reducing the venture capital pool for AI, potentially driving away top talent and causing AI research and development centers to relocate elsewhere. Instead of increasing restrictions, a smarter policy would be to continue utilizing CFIUS risk mitigation measures in a non-discriminatory manner, while increasing government funding for AI research and development and increasing visas for science and technology graduate students who are foreign nationals.
- Published
- 2018
13. Boeing v. Bombardier: Material Injury Analysis at the International Trade Commission
- Author
-
Justin Shields
- Subjects
Product (business) ,Multinational corporation ,business.industry ,Countervailing duties ,Market price ,Subsidy ,Business ,Competitor analysis ,International trade ,Protectionism ,Purchasing - Abstract
On February 13, 2018, the U.S. International Trade Commission (ITC) determined unanimously that Boeing, the U.S. manufacturer of commercial aircraft, was not materially injured or threatened with material injury by reason of commercial aircraft imported from Canada by Bombardier. By finding that material injury did not exist, Bombardier was able to complete the sale of its C Series jets to Delta Airlines without the imposition of antidumping or countervailing duties. Boeing claimed that the Canadian government’s illegal subsidization of the C Series program allowed Bombardier to sell its products in the U.S. market at an artificially low price. During its material injury analysis, the ITC found however, that Bombardier’s C Series imports would not displace sales of Boeing’s competing product, that the “launch-pricing” Bombardier offered to Delta would not set the market price for future sales of such product, and that importation of the C Series would not adversely impact future sales and development of Boeing’s competitor product, the 737 Max 7. The decision had a significant impact not only on both parties, but on the commercial aircraft industry as a whole, and international trade policy. While the dispute caused Bombardier to partner with Airbus to ensure the viability of the C Series, Boeing responded by purchasing the Brazilian jet manufacturer Embraer, one of Bombardier’s competitors. The decision also helped to smooth U.S.-Canada trade relations, supported the theory that multinational supply chains reduce incentives for tariffs, and reinforced the independence of the ITC. Moreover, the decision affirmed the U.S. commitment to a rules-based global trade system in spite of recent political support for increased protectionism.
- Published
- 2018
14. Trimming the Sails: Philippine Interests and Post-Arbitration Strategy in the South China Sea
- Author
-
Justin Shields
- Subjects
National security ,Sovereignty ,business.industry ,Political science ,Political economy ,Deference ,Law of the sea ,International law ,China ,Geopolitics ,business ,Militarization - Abstract
The election of populist President Rodrigo Duterte brought about a significant change in the South China Sea policy of the Philippines. Whereas the previous administration preferred to assert its sovereign rights to portions of the South China Sea through an arbitration action against China, the new president has sought reconciliation with China to address conflicting sovereignty claims. This article argues that although Duterte’s new strategy has secured some short-term gains, it has been largely ineffective in securing the long-term national interests of the Philippines in the South China Sea. Not only have the Chinese infrastructure loans that Duterte was promised in exchange for his policy shift failed to materialize, his deference to China’s interests threatens to jeopardize the fishing rights, natural resource rights, and national security interests of the Philippines. Philippine fishermen, a crucial sector of the economy, now have access to Scarborough Shoal, but without any formal agreement, Chinese naval vessels retain control over the area and can restrict access at their discretion. In addition, Philippine rights to exploitation of certain South China Sea oil and natural gas resources, which are critical to fueling the future Philippine economy, have been sacrificed in order to placate China’s preference for joint development. Finally, Duterte’s failure to push back against Chinese militarization of the South China Sea in the interest of reconciliation, has worsened the national security situation of the Philippines and weakened its ability to defend its interests in the area. President Duterte’s strategic gamble that deference to China will allow the Philippines access to the region’s resources while side-stepping the issue of sovereignty carries with it the risk of implicitly recognizing China’s claims and forfeiting legitimate Philippine claims to the region. If China does not pay a price for its assertive behavior in the South China Sea, it will continue to dictate the terms of engagement in the region to the detriment of smaller nations like the Philippines. *Previously titled - Trimming the Sails: Philippine Interests and Post-Arbitration Strategy in the South China Sea.
- Published
- 2017
15. Highly bioavailable silibinin nanoparticles inhibit HCV infection
- Author
-
Cheng Jeng Tai, Chun Ching Lin, Chueh Yao Chung, Ming Hong Yen, Chih Chan Lin, Liang Tzung Lin, Ching Hsuan Liu, Wen Chan Hsu, D. Lorne Tyrrell, Chen Jei Tai, Shun Pang Chang, Justin Shields, Christopher D. Richardson, and Alagie Jassey
- Subjects
0301 basic medicine ,Male ,Silibinin ,Hepacivirus ,Pharmacology ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Delivery Systems ,Pharmacokinetics ,In vivo ,Oral administration ,medicine ,Flavonolignan ,Animals ,Humans ,Cells, Cultured ,Hepatitis ,Life Cycle Stages ,Chemistry ,Gastroenterology ,Hepatitis C ,medicine.disease ,Bioavailability ,Rats ,030104 developmental biology ,Silybin ,Hepatocytes ,030211 gastroenterology & hepatology ,Nanospheres ,Silymarin - Abstract
Objective Silibinin is a flavonolignan that is well established for its robust antiviral activity against HCV infection and has undergone several clinical trials for the management of hepatitis C. Despite its potency, silibinin suffers from poor solubility and bioavailability, restricting its clinical use. To overcome this limitation, we developed highly bioavailable silibinin nanoparticles (SB-NPs) and evaluated their efficiency against HCV infection. Design SB-NPs were prepared using a nanoemulsification technique and were physicochemically characterised. Infectious HCV culture systems were used to evaluate the influence of SB-NP on the virus life cycle and examine their antioxidant activity against HCV-induced oxidative stress. The safety profiles of SB-NP, in vivo pharmacokinetic studies and antiviral activity against infection of primary human hepatocytes were also assessed. Results SB-NP consisted of nanoscale spherical particles ( 97% efficiency and increasing the compound9s solubility by >75%. Treatment with SB-NP efficiently restricted HCV cell-to-cell transmission, suggesting that they retained silibinin9s robust anti-HCV activity. In addition, SB-NP exerted an antioxidant effect via their free radical scavenging function. Oral administration of SB-NP in rodents produced no apparent in vivo toxicity, and pharmacokinetic studies revealed an enhanced serum level and superior biodistribution to the liver compared with non-modified silibinin. Finally, SB-NP efficiently reduced HCV infection of primary human hepatocytes. Conclusions Due to SB-NP9s enhanced bioavailability, effective anti-HCV activity and an overall hepatoprotective effect, we suggest that SB-NP may be a cost-effective anti-HCV agent that merits further evaluation for the treatment of hepatitis C.
- Published
- 2016
16. Rapamycin-mediated suppression of renal cyst expansion in del34Pkd1−/−mutant mouse embryos: An investigation of the feasibility of renal cyst prevention in the foetus
- Author
-
Michael R. Eccles, Cherie Stayner, Justin Shields, Thomas Weimbs, Lynn Slobbe, and Jonathan M. Shillingford
- Subjects
medicine.medical_specialty ,Kidney ,PKD1 ,urogenital system ,business.industry ,Kidney development ,General Medicine ,urologic and male genital diseases ,medicine.disease ,Kidney cysts ,female genital diseases and pregnancy complications ,Cystic kidney disease ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,In utero ,Internal medicine ,embryonic structures ,Polycystic kidney disease ,Medicine ,Cyst ,medicine.symptom ,business - Abstract
Aim: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice. Methods: Pregnant Pkd1+/− female mice (mated with Pkd1+/− male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. Results: Numerous cysts were present in Pkd1−/− kidneys, which were twice the weight of wild-type kidneys. Cyst size was reduced by a third in rapamycin-treated Pkd1−/− kidney sections and kidney mass was reduced to near wild-type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin-treated mice but some lethality was observed in Pkd1−/− null embryos. Conclusion: Rapamycin treatment reduces cyst formation in Pkd1−/− mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin-associated lethality limits its usefulness as a treatment in utero.
- Published
- 2012
17. Screening of drugs to counteract human papillomavirus 16 E6 repression of E-cadherin expression
- Author
-
Justin Shields, Zarina J. D’Costa, Charles M. Matthews, Merilyn Hibma, and Cheng-Mee Leong
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Indoles ,Biology ,Decitabine ,Antiviral Agents ,Immune system ,medicine ,Humans ,Pharmacology (medical) ,Cell adhesion ,Cytotoxicity ,Psychological repression ,Pharmacology ,Cervical cancer ,Epidermis (botany) ,Cadherin ,Oncogene Proteins, Viral ,DNA Methylation ,Cadherins ,HCT116 Cells ,medicine.disease ,Repressor Proteins ,Tamoxifen ,Oncology ,Doxorubicin ,Immunology ,Azacitidine ,medicine.drug - Abstract
Persistent infections with certain high-risk human papillomavirus (HPV) types such as 16 and 18 can result in the development of cervical cancer. Neither of the two prophylactic vaccines against HPV16 and 18 that are in current use have any therapeutic efficacy for prevalent HPV infections. Ablative therapy is widely used for the treatment of HPV cervical dysplasia however disease recurrence is a widely recognized problem. Thus there is a continuing need for therapeutic approaches for the treatment of HPV infections. The HPV16 E6 viral oncoprotein represses surface expression of the cellular adhesion molecule, E-cadherin. Reduced E-cadherin expression on HPV-infected keratinocytes is associated with lowered numbers of antigen-presenting Langerhans cells in the infected epidermis, potentially reducing immune surveillance for HPV. Four chemicals reported to up-regulate E-cadherin were screened for their ability to counteract E6 repression of surface E-cadherin. 5-Aza-2'-deoxycytidine (AzaDC), a DNA methyltransferase inhibitor, and Indole-3-carbinol (I3C), reported to increase E-cadherin through a p21(Waf1/Cip1)-dependent mechanism, had low cytotoxicity and increased or restored E-cadherin expression and adhesive function in HPV16 E6 expressing HCT116 cells. Doxorubicin, also known to induce p21(Waf1/Cip1), increased E-cadherin in E6 expressing cells but had some associated cytotoxicity. Tamoxifen, which can restore adhesive function of surface E-cadherin, was ineffective in counteracting E6 repression of E-cadherin. AzaDC and I3C both show potential to restore antigen-presenting cells to HPV infected skin by antagonizing E6 repression of E-cadherin, thereby counteracting an important immune evasion mechanism of HPV16 and reinstating immune function at the infected site.
- Published
- 2012
18. Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry
- Author
-
Rodney S. Russell, Chueh Yao Chung, Shun Pang Chang, Ming Hong Yen, Liang Tzung Lin, D. Lorne Tyrrell, Ting Chun Hung, Chih Chan Lin, Chun Ching Lin, Christopher D. Richardson, Wen Chan Hsu, Justin Shields, and Chien Feng Li
- Subjects
Male ,Hepatitis C virus ,Hepacivirus ,Biology ,medicine.disease_cause ,Virus Replication ,Antiviral Agents ,Virus ,Neutralization ,Cell Line ,Rats, Sprague-Dawley ,Multiplicity of infection ,Viral life cycle ,Viral entry ,medicine ,Animals ,Humans ,Oleanolic Acid ,Hepatitis B virus ,Hepatology ,Plant Extracts ,Virion ,virus diseases ,Saponins ,Virus Internalization ,biology.organism_classification ,Virology ,Hepatitis C ,digestive system diseases ,Bupleurum ,Liver Transplantation ,Rats ,Vesicular stomatitis virus ,Hepatocytes - Abstract
Background & Aims A vaccine against hepatitis C virus (HCV) is unavailable and cost-effective antivirals that prevent HCV infection and re-infection, such as in the transplant setting, do not exist. In a search for novel and economical prophylactic agents, we examined the antiviral activity of saikosaponins (SSa, SSb2, SSc, and SSd) from Bupleurum kaoi root (BK) as entry inhibitors against HCV infection. Methods Infectious HCV culture systems were used to examine the effect of saikosaponins on the complete virus life cycle (entry, RNA replication/translation, and particle production). Antiviral activity against various HCV genotypes, clinical isolates, and infection of primary human hepatocytes were also evaluated. Results BK and the saikosaponins potently inhibited HCV infection at non-cytotoxic concentrations. These natural agents targeted early steps of the viral life cycle, while leaving replication/translation, egress, and spread relatively unaffected. In particular, we identified SSb2 as an efficient inhibitor of early HCV entry, including neutralization of virus particles, preventing viral attachment, and inhibiting viral entry/fusion. Binding analysis, using soluble viral glycoproteins, demonstrated that SSb2 acted on HCV E2. Moreover, SSb2 inhibited infection by several genotypic strains and prevented binding of serum-derived HCV onto hepatoma cells. Finally, treatment with the compound blocked HCV infection of primary human hepatocytes. Conclusions Due to its potency, SSb2 may be of value for development as an antagonist of HCV entry and could be explored as prophylactic treatment during the course of liver transplantation.
- Published
- 2014
19. Functional changes, increased apoptosis, and diminished nuclear factor-kappaB activity of myeloid dendritic cells during chronic hepatitis C infection
- Author
-
D. Lorne Tyrrell, Li Zhao, and Justin Shields
- Subjects
Male ,Myeloid ,Hepatitis C virus ,T-Lymphocytes ,Immunology ,Antigen presentation ,Blotting, Western ,Apoptosis ,Biology ,medicine.disease_cause ,Immune tolerance ,Immunopathology ,medicine ,In Situ Nick-End Labeling ,Immunology and Allergy ,Humans ,Myeloid Cells ,Cells, Cultured ,Microscopy, Confocal ,NF-kappa B ,General Medicine ,Hepatitis C ,Dendritic Cells ,HLA-DR Antigens ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Flow Cytometry ,medicine.anatomical_structure ,Female ,I-kappa B Proteins ,B7-2 Antigen ,Viral hepatitis - Abstract
Approximately 70% of patients infected with hepatitis C virus (HCV) develop chronic infections, which have been reported to be caused by impaired specific T-cell responses. Myeloid dendritic cells (mDCs) are important antigen-presenting cells that regulate T-cell responses, however their role during chronic hepatitis C (CHC) is not fully understood. In this study, we found that the ability of mDCs to stimulate T-cell responses was impaired in CHC patients. Furthermore, mDCs from CHC patients underwent apoptosis at a higher rate than mDCs from healthy donors. Nuclear factor-kappaB activity, which is critical for mDC function and apoptosis prevention, was diminished in mDCs from CHC patients. In conclusion, mDCs from CHC patients demonstrated functional changes with increased apoptosis, and diminished nuclear factor-kappaB activity. These changes may contribute to the impaired specific T-cell responses in CHC patients.
- Published
- 2009
20. Erratum to 'Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry' [J Hepatol 2015;62:541–548]
- Author
-
Shun Pang Chang, Wen Chan Hsu, Chun Ching Lin, Ming Hong Yen, Liang Tzung Lin, Justin Shields, Chien Feng Li, Ting Chun Hung, Rodney S. Russell, Christopher D. Richardson, D. Lorne Tyrrell, Chih Chan Lin, and Chueh Yao Chung
- Subjects
Hepatology ,Hepatitis C virus ,medicine ,Biology ,medicine.disease_cause ,Virology ,Terpenoid - Published
- 2015
21. Hepatitis C Virus-Induced Cytoplasmic Organelles Use the Nuclear Transport Machinery to Establish an Environment Conducive to Virus Replication
- Author
-
Justin Shields, Rineke Steenbergen, Aviad Levin, Christopher J. Neufeldt, Richard W. Wozniak, Daniel Pang, Michael A. Joyce, and D. Lorne Tyrrell
- Subjects
QH301-705.5 ,Immunology ,Active Transport, Cell Nucleus ,Hepacivirus ,Biology ,Virus Replication ,Microbiology ,Cell Line ,Protein–protein interaction ,03 medical and health sciences ,Virology ,Genetics ,medicine ,Humans ,Biology (General) ,Nuclear membrane ,Nuclear pore ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,030302 biochemistry & molecular biology ,Intracellular Membranes ,RC581-607 ,Hepatitis C ,3. Good health ,Cell biology ,medicine.anatomical_structure ,Viral replication ,Membrane protein ,Cytoplasm ,Host cell cytoplasm ,Nuclear Pore ,Parasitology ,Immunologic diseases. Allergy ,Nuclear transport ,Research Article - Abstract
Hepatitis C virus (HCV) infection induces formation of a membranous web structure in the host cell cytoplasm where the viral genome replicates and virions assemble. The membranous web is thought to concentrate viral components and hide viral RNA from pattern recognition receptors. We have uncovered a role for nuclear pore complex proteins (Nups) and nuclear transport factors (NTFs) in the membranous web. We show that HCV infection leads to increased levels of cytoplasmic Nups that accumulate at sites enriched for HCV proteins. Moreover, we detected interactions between specific HCV proteins and both Nups and NTFs. We hypothesize that cytoplasmically positioned Nups facilitate formation of the membranous web and contribute to the compartmentalization of viral replication. Accordingly, we show that transport cargo proteins normally targeted to the nucleus are capable of entering regions of the membranous web, and that depletion of specific Nups or Kaps inhibits HCV replication and assembly., Author Summary Hepatitis C virus (HCV) is a positive strand RNA virus and is a major cause of liver disease worldwide, affecting more than 170 million individuals. Infection of cells with HCV leads to rearrangement of cytoplasmic host cell membranes into viral replication and assembly complexes collectively known as the membranous web. This membranous web is thought to be involved in concentrating viral components and immune evasion, though the mechanisms by which these functions are achieved remains an important question in the field. Here, we report that nuclear envelope structures that transport macromolecules into and out of the nucleus, termed nuclear pore complexes (NPCs), are also present in the membranous web of cells infected with HCV and other positive strand RNA viruses. Our results suggest that these NPCs function to regulate access of proteins into the interior of the membranous web, thus contributing to the establishment of an environment conducive to viral replication and viral immune evasion. Consistent with this idea, we show that NPC proteins are required for HCV assembly. Our discovery that nuclear transport proteins play a role in HCV replication, and potentially other viral infections, may lead to the discovery of new targets for antiviral therapies.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.