Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.

In this study, we identified four amantadine-resistant M2 mutants among avian and human influenza A H5N1 strains circulating between 2002 to 2019: the single S31N and V27A mutants, and the S31N/L26I and S31N/V27A double mutants. Herein, utilizing two-electrode voltage clamp (TEVC) assays, we screened a panel of structurally diverse M2 inhibitors against these single and double mutant channels. Three compounds 6, 7, and 15 were found to significantly block all three M2 mutants: M2-S31N, M2-S31N/L26I, and M2-S31N/V27A. Using recombinant viruses generated from reverse genetics, we further showed that these compounds also inhibited the replication of recombinant viruses harboring either the single S31N or double S31N/L26I and S31N/V27A mutants. This work represents the first example in developing antivirals by targeting the drug-resistant double mutants of M2 proton channels. PMID: 31669761 [PubMed - as supplied by publisher]
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research

Related Links:

Conclusions: Human challenge studies and systems biology approaches are important tools that should be used in concert to advance our understanding of influenza infection and provide targets for novel therapeutics and immunizations. Introduction Although influenza virus was recognized as an important pathogen over a century ago, influenza continues to cause a significant burden of disease. In the United States alone, it's estimated that in the 2017–2018 season there were 959,000 hospitalizations related to influenza illness, and 79,400 deaths (CDC, 2018). Worldwide, WHO estimates that annual influenza...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
Jennifer M. Rudd1, Sivasami Pulavendran1, Harshini K. Ashar1, Jerry W. Ritchey1, Timothy A. Snider1, Jerry R. Malayer1, Montelongo Marie1, Vincent T. K. Chow2 and Teluguakula Narasaraju1* 1Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States2Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore Exaggerated host innate immune responses have been implicated in severe influenza pneumonia. We have previously demonstrated that excessive neutrophils recruited during in...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
ahesh Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways ...
Source: Viruses - Category: Virology Authors: Tags: Review Source Type: research
Authors: Mandil A, Bresee J, Tageldin MA, Azad TM, Khan W Abstract Infectious diseases continue to represent a significant threat to global health security, particularly in the context of increasing globalization, interconnectedness and interdependence. Chief among such threats are influenza viruses and other respiratory pathogens, such as Middle East Respiratory Syndrome coronavirus (MERS-CoV), because of their risk of high transmissibility and acuity of illness. Annual epidemics of seasonal influenza cause an estimated 3-5 million cases of severe illness and more than 500 000 deaths, with the prospect of pandemic...
Source: Eastern Mediterranean Health Journal - Category: Middle East Health Tags: East Mediterr Health J Source Type: research
Abstract Bird to human transmission of high pathogenicity avian influenza virus (HPAIV) poses a significant risk of triggering a flu pandemic in the human population. Therefore, vaccination of susceptible poultry during an HPAIV outbreak might be the best remedy to prevent such transmissions. To this end, suitable formulations and an effective mass vaccination method that can be translated to field settings needs to be developed. Our previous study in chickens has shown that inhalation of a non-adjuvanted dry powder influenza vaccine formulation during normal breathing results in partial protection against lethal ...
Source: European Journal of Pharmaceutics and Biopharmaceutics - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Biopharm Source Type: research
Abstract The limited protection of current commerical vaccines necessitates the investigation of novel vaccine strategies for unpredictable outbreaks. To investigate the feasibility of using vaccines derived from Group 1 influenza A virus to induce broadly cross-reactive immune responses against multiple influenza subtypes, we tested a panel of sequential 4-dose immunization regimens in mice. Mice were treated with inactivated (seasonal H1N1, pandemic H1N1 and H5N1) and vaccinia virus-based H5N1 live-attenuated vaccines in different combinations. Mice were then challenged by viruses of either Group 1 (H1N1) or Gro...
Source: Virology - Category: Virology Authors: Tags: Virology Source Type: research
Since March 2013, when the avian influenza A(H7N9) virus infection was first detected in humans, a total of 1567 laboratory-confirmed human cases, including at least 615 deaths1, have been reported to WHO (Figure 1) in accordance with the International Health Regulations (2005). In the latest wave (the 6th wave since Oct 2017), only three human cases have been detected; meanwhile there have been generally fewer A(H7N9) virus detections in poultry and environment samples, according to various reports from mainland China and China, Hong Kong SAR. WHO has been monitoring the situation, and conducting risk assessments2 through...
Source: WHO Avian Influenza - Category: Infectious Diseases Tags: avian influenza [subject], bird flu, avian flu, fowl plague, influenza in birds, avian bird flu, h5n1, disease outbreaks [subject], outbreak, outbreaks, epidemics, pandemic, disease control, influenza [subject], flu, seasonal influenza, pandemic influenza Source Type: news
DAVID E. BLOOM is the Clarence James Gamble Professor of Economics and Demography, DANIEL CADARETTE is a research assistant, and JP SEVILLA is a research associate, all at Harvard University’s T.H. Chan School of Public Health.By David E. Bloom, Daniel Cadarette and JP SevillaWASHINGTON DC, Jul 3 2018 (IPS)Infectious diseases and associated mortality have abated, but they remain a significant threat throughout the world.We continue to fight both old pathogens, such as the plague, that have troubled humanity for millennia and new pathogens, such as human immunodeficiency virus (HIV), that have mutated or spilled over ...
Source: IPS Inter Press Service - Health - Category: International Medicine & Public Health Authors: Tags: Active Citizens Development & Aid Economy & Trade Global Headlines Health TerraViva United Nations Source Type: news
AbstractThis work aimed to analyze the herd immunity to influenza among a Russian population living in regions with an increased risk of emergence of viruses with pandemic potential, and to isolate and investigate virus strains from severe influenza cases, including fatal cases, during the 2016 –2017 epidemic season. In November 2016 – March 2017 highly pathogenic influenza outbreaks were registered in Russia among wild birds and poultry. No cases of human infection were registered. Analysis of 760 sera from people who had contact with infected or perished birds revealed the presence o f antibodies to A(H5N1) v...
Source: Archives of Virology - Category: Virology Source Type: research
In this study, we attempted to generate a high growth influenza vaccine strain in MDCK cells using an A/Puerto/8/1934 (H1N1) vaccine seed strain. Following 48 serial passages with four rounds of virus plaque purification in MDCK cells, we were able to select several MDCK-adapted plaques that could grow over 108 PFU/ml. Genetic characterization revealed that these viruses mainly had amino acid substitutions in internal genes and exhibited higher polymerase activities. By using of a series of Rg viruses, we demonstrated the essential residues of each gene and identified a set of high-growth strains in MDCK cells (PB1D153N, M...
Source: Journal of Microbiology and Biotechnology - Category: Biotechnology Authors: Tags: J Microbiol Biotechnol Source Type: research
More News: Amantadine | Bird Flu | Drugs & Pharmacology | Flu Pandemic | Flumadine | Genetics | H5N1 | Influenza | Outbreaks | Pandemics | Rimantadine | Study | Symmetrel