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viral inhibitor

Pek Yoke Chong, J Brad Shotwell, John F Miller, Daniel J Price, Andy Maynard, Christian Voitenleitner, Amanda Mathis, Shawn Williams, Jeffrey Pouliot, Katrina Creech, Feng Wang, Jing M Fang, Huichang Zhang, Vincent Tai, Elizabeth Turner, Kristen M Kahler, Renae Crosby, Andrew J Peat
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which a N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein we describe second generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons...
February 14, 2019: Journal of Medicinal Chemistry
Melanie R Hassler, Shahrokh F Shariat, Francesco Soria
PURPOSE OF REVIEW: To give an overview of current options for conservative treatment of patients failing intravesical bacillus Calmette-Guerin (BCG) and to discuss emerging approaches with potential future clinical applications. RECENT FINDINGS: Radical cystectomy is the standard-of-care for patients failing BCG therapy. In patients unfit or unwilling to undergo surgery, salvage therapy options could be proposed with the aim to offer local cancer control and prevent progression to muscle-invasive disease...
February 11, 2019: Current Opinion in Urology
Pieter Vrijens, Sam Noppen, Talitha Boogaerts, Els Vanstreels, Roberto Ronca, Paola Chiodelli, Manon Laporte, Evelien Vanderlinden, Sandra Liekens, Annelies Stevaert, Lieve Naesens
The possible resistance of influenza virus against existing antiviral drugs calls for new therapeutic concepts. One appealing strategy is to inhibit virus entry, in particular at the stage of internalization. This requires a better understanding of virus-host interactions during the entry process, including the role of receptor tyrosine kinases (RTKs). To search for cellular targets, we evaluated a panel of 276 protein kinase inhibitors in a multicycle antiviral assay in Madin-Darby canine kidney cells. The RTK inhibitor Ki8751 displayed robust anti-influenza A and B virus activity and was selected for mechanistic investigations...
February 14, 2019: Journal of General Virology
Joseph W Jackson, Trevor J Hancock, Pranay Dogra, Ravi Patel, Ravit Arav-Boger, Angela D Williams, Stephen J Kennel, Jonathan S Wall, Tim E Sparer
Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease following in utero exposure, during primary infection, or latent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation...
February 13, 2019: MSphere
Robert van Domselaar, Duncan T Njenda, Rohit Rao, Anders Sönnerborg, Kamalendra Singh, Ujjwal Neogi
Human immunodeficiency virus type 1 subtype C (HIV-1C) has a natural deletion of a YPxL motif in its Gag-p6 late domain. This domain mediates the binding of Gag to host cell protein ALIX and subsequently facilitates viral budding. In a subset of HIV-1C infected individuals, the tetrapeptide insertion PYxE has been identified at the deleted YPxL motif site. Here, we report the consequences of PYxE insertion on the interaction with ALIX and the relevance regarding replication fitness and drug sensitivity. In our three HIV-1C cohorts, PYKE and PYQE were most prevalent among PYxE variants...
February 13, 2019: Journal of Virology
Christopher M Goodwin, Joshua Munger
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes disease in immunosuppressed populations. HCMV has a complex relationship with innate immune signaling pathways. Specifically, HCMV has been found to block some aspects of inflammatory signaling while benefiting from others. Through analysis of knockout cell lines targeting the NFκB regulatory kinases IKKα and IKKβ, we find that the IKK kinases are host restriction factors that contribute to cytokine-mediated resistance to viral infection, limit the initiation of HCMV infection, and attenuate viral cell-to-cell spread...
February 13, 2019: Journal of Virology
Jennifer C Becker, Sharon J Tollefson, David Weaver, John V Williams
Human metapneumovirus, a paramyxovirus discovered in 2001, is a major cause of lower respiratory infection in adults and children worldwide. There are no licensed vaccines or drugs for human metapneumovirus. We developed a fluorescent, cell-based medium-throughput screening assay for human metapneumovirus that captures inhibitors of all stages of the viral lifecycle except budding of progeny virus particles from the cell membrane. We optimized and validated the assay and performed a successful medium-throughput screening...
January 2019: Antiviral Chemistry & Chemotherapy
Amin S Hassan, David F Bibby, Shalton M Mwaringa, Clara A Agutu, Kennedy K Ndirangu, Eduard J Sanders, Patricia A Cane, Jean L Mbisa, James A Berkley
BACKGROUND: The epidemiology of HIV-1 drug resistance (HIVDR) determined by Sanger capillary sequencing, has been widely studied. However, much less is known about HIVDR detected using next generation sequencing (NGS) methods. We aimed to determine the presence, persistence and effect of pre-treatment HIVDR variants detected using NGS in HIV-1 infected antiretroviral treatment (ART) naïve participants from rural Coastal Kenya. METHODS: In a retrospective longitudinal study, samples from HIV-1 infected participants collected prior [n = 2 time-points] and after [n = 1 time-point] ART initiation were considered...
2019: PloS One
Shamus P Keeler, Benjamin J Gerovac, Kangyun Wu, Xinyu Wang, Joshua R Chartock, Derek E Byers, Arthur G Romero, Michael J Holtzman
New studies of chronic obstructive pulmonary disease (COPD) are revealing the key role of airway epithelial cells and innate immune cells in the initiation, exacerbation, and progression of airway disease. An emerging scheme focuses on expansion of airway progenitor epithelial cells that feed forward for a type 2 immune response and consequent IL-13-driven mucus production that is linked to the morbidity and mortality of COPD. Analysis of human airway progenitor epithelial cells and airway tissue shows that IL-13 signaling to MUC5AC mucin gene expression relies on specific activation of mitogen-activated protein kinase 13, providing a druggable target for attenuating mucus production in the setting of viral infection and other inhaled stimuli of airway inflammation...
December 2018: Annals of the American Thoracic Society
Dmitry Kostyushev, Anastasiya Kostyusheva, Sergey Brezgin, Dmitry Zarifyan, Anastasiya Utkina, Irina Goptar, Vladimir Chulanov
Chronic hepatitis B is a severe liver disease caused by hepatitis B virus (HBV) infection. Covalently closed circular DNA (cccDNA), a super-spiralized, double-stranded form of the HBV genome, is the major determinant of viral persistence. CRISPR/Cas9 nucleases have been recently shown to introduce double-stranded DNA breaks into HBV cccDNA. The inflicted damage results predominantly in erroneous repair of cccDNA by non-homologous end-joining (NHEJ). NHEJ has been suggested to enhance anti-HBV activity of CRISPR/Cas9 and increase cccDNA mutation...
February 12, 2019: Scientific Reports
Felicitas Bossler, Bianca J Kuhn, Thomas Günther, Stephen J Kraemer, Prajakta Khalkar, Svenja Adrian, Claudia Lohrey, Angela Holzer, Mitsugu Shimobayashi, Matthias Dürst, Arnulf Mayer, Frank Rösl, Adam Grundhoff, Jeroen Krijgsveld, Karin Hoppe-Seyler, Felix Hoppe-Seyler
Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia...
February 12, 2019: MBio
Mrutyunjaya Parida, Kyle A Nilson, Ming Li, Christopher B Ball, Harrison A Fuchs, Christine K Lawson, Donal S Luse, Jeffery L Meier, David H Price
The large genome of human cytomegalovirus (HCMV) is transcribed by RNA polymerase II (Pol II). However, it is not known how closely this betaherpesvirus follows host transcriptional paradigms. We applied PRO-Seq and PRO-Cap methods to profile and quantify transcription initiation and productive elongation across the host and virus genomes in late infection. A major similarity between host transcription and viral transcription is that treatment of cells with the P-TEFb inhibitor flavopiridol preempts virtually all productive elongation, which otherwise covers most of the HCMV genome...
February 12, 2019: MBio
Alexis Bouin, Paul-Antoine Gretteau, Michel Wehbe, Fanny Renois, Yohan N'Guyen, Nicolas Leveque, Michelle N Vu, Steven Tracy, Nora M Chapman, Patrick Bruneval, Paul Fornes, Bert L Semler, Laurent Andreoletti
BACKGROUND: Group B enteroviruses are common causes of acute myocarditis which can be a precursor of chronic myocarditis and dilated cardiomyopathy (DCM), leading causes of heart transplantation. To date, the specific viral functions involved in the development of DCM remain unclear. METHODS: Total RNA from cardiac tissue of patients suffering from DCM was extracted, and sequences corresponding to the 5' termini of enterovirus RNAs were identified. Following NexGen RNA sequencing, viral cDNA clones mimicking the enterovirus RNA sequences found in patient tissues were generated in vitro, and their replication and impact on host cell functions were assessed on primary human cardiac cells in culture...
February 13, 2019: Circulation
Venice Du Pont, Richard K Plemper, Matthias J Schnell
Rabies virus (RABV) constitutes a major social and economic burden associated with 60 000 deaths annually worldwide. Although pre-exposure and post-exposure treatment options are available, they are efficacious only when initiated before the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals...
February 9, 2019: Current Opinion in Virology
Shaoqing Zang, Xin Zhang, Chen Li, Liqun Wang, Jingguang Wei, Qiwei Qin
Phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α) occurs under a variety of conditions, including viral infection. Heme-regulated inhibitor (HRI) is an eIF2α kinase that modifies this phosphorylation. In this study, a HRI homologue (EcHRI) from the orange-spotted grouper (Epinephelus coioides) was cloned and its roles during fish viral infection were characterized. EcHRI encodes a 664-amino acid polypeptide that shares a high degree of similarity with HRIs from other species. Quantitative real-time polymerase chain reaction analysis indicated that EcHRI was distributed in all examined tissues...
February 9, 2019: Fish & Shellfish Immunology
Inmaculada Jarrin, Ines Suarez-Garcia, Cristina Moreno, Maria Tasias, Jorge Del Romero, Rosario Palacios, Joaquim Peraire, Miguel Gorgolas, Santiago Moreno
BACKGROUND: We compared time to treatment change (TC), viral suppression (VS) and change in CD4+ T-cell counts of first-line antiretroviral regimens (ART). METHODS: We analyzed HIV treatment-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) initiating the most commonly used ART regimens from September 2014 to November 2015. We used proportional hazards models on the sub-distribution hazard to estimate sub-distribution hazard ratios (sHR) for time to TC, logistic regression to estimate odds ratios (ORs) for VS (viral load<50 copies/ml), and linear regression to assess mean differences in CD4 changes from ART initiation...
February 12, 2019: Antiviral Therapy
Althaf Shaik, Harshit Kumar Agarwal, Rashmi Bhakuni, Sivapriya Kirubakaran
PDE5A is a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. PDE5A takes part in several physiological and pathological pathways and is considered an important drug target. Currently, PDE5 inhibitors (ex; Sildenafil, Tadalafil) available in the market are not only being used for the treatment of erectile dysfunction but at the same time, they are also in the clinical trials being investigated as anticancer agents. In this work, we have examined pyrazolo [4,3-c]quinolin-3-ones as PDE5A inhibitors...
February 8, 2019: Current Topics in Medicinal Chemistry
Myosotys Rodriguez, Jessica Lapierre, Chet Raj Ojha, Shashank Pawitwar, Mohan Kumar Muthu Karuppan, Fatah Kashanchi, Nazira El-Hage
Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure...
February 11, 2019: Journal of Neurovirology
Karl J Fischer, Vijaya Kumar Yajjala, Shruti Bansal, Christopher Bauer, Ruiling Chen, Keer Sun
Methicillin-resistant Staphylococcus aureus has emerged as a significant contributor to morbidity and mortality associated with influenza infection. In this study, we show in a mouse model that preceding influenza infection promotes S. aureus resistance to killing by antibiotics. This resistance coincides with influenza-induced accumulation of inflammatory monocytes in the lung. CCR type 2 (CCR2) is responsible for pulmonary monocyte recruitment after influenza infection. We found that antibiotic-treated Ccr2-deficient (Ccr2-/- ) mice exhibit significantly improved bacterial control and survival from influenza and methicillin-resistant S...
February 11, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Nadejda Beliakova-Bethell, Amey Mukim, Cory H White, Savitha Deshmukh, Hosiana Abewe, Douglas D Richman, Celsa A Spina
Histone deacetylase (HDAC) inhibitors (HDACi) have been widely tested in clinical trials for their ability to reverse HIV latency, but have yielded only limited success. One HDACi, suberoylanilide hydroxamic acid (SAHA), exhibits off-target effects on host gene expression predicted to interfere with induction of HIV transcription. Romidepsin (RMD) has higher potency and specificity for class I HDACs implicated in maintaining HIV provirus in the latent state. More robust HIV reactivation has indeed been achieved with RMD use ex vivo than with SAHA; however, reduction of viral reservoir size has not been observed in clinical trials...
February 11, 2019: Journal of Biological Chemistry
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