Special Issue "Recent Strategies in Anti-influenza Therapeutics"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 28 February 2022.

Special Issue Editor

Dr. Serena Massari
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
Interests: medicinal chemistry; drug discovery; small molecules; antiviral agents; protein–protein interaction inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

As demonstrated by COVID-19, viruses are able to generate pandemics with a devastating socioeconomic impact in the world. In 1918, humanity witnessed the deadliest pandemic in human history, the Spanish flu, which caused extraordinary mortality around the globe. There is great concern that influenza viruses (flu) may cause another unpredictable devastating pandemic, perpetuated by the continuous emergence of new fluA strains. Of particular concern to public health are the avian fluA strains H5N1 and H7N9, human infections of which are associated with high mortality.  Vaccination remains the main prophylactic strategy for controlling flu infection, but a universal flu vaccine that confers broad and long-term protection does not exist. Regarding the therapeutic armamentarium, almost 20 years from the approval of the neuraminidase (NA) inhibitors oseltamivir and zanamivir, they remain the only antiviral drugs of wide clinical use. The emergence of widespread resistance has caused M2 ion channel inhibitors to no longer be recommended, and the two recently approved NA inhibitors have important limitations. Nevertheless, during recent years, major breakthroughs have been made in the development of new anti-flu agents endowed with a different mode of action. Several agents have entered the clinical pipeline, many of which target the viral hemagglutinin and polymerase complex. Noteworthy are the compounds targeting the three subunits of the viral polymerase complex, such as the nucleoside analog favipiravir already approved in Japan, the PA endonuclease inhibitor baloxavir marboxil recently approved in both Japan and the USA, and the PB2 cap-binding inhibitor pimodivir that is in late-phase clinical trials.  To achieve a comprehensive understanding of the progress made and the current trends in the development of new anti-flu therapeutics, the journal Pharmaceuticals invites renowned experts in the field to contribute research articles or reviews. This Special Issue, entitled “Recent Strategies in Anti-Influenza Therapeutics”, will focus on the development of new anti-flu agents, but also on studies aimed at understanding the molecular mechanisms of flu replication that are essential in order to identify new therapeutic targets.

Dr. Serena Massari
Guest Editor

Manuscript Submission Information

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Keywords

  • influenza virus
  • anti-influenza agents
  • vaccines
  • drug discovery
  • drug development

Published Papers (4 papers)

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Research

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Article
CRISPR/CasRx Proof-of-Concept for RNA Degradation: A Future Tool against RNA Viruses?
Pharmaceuticals 2022, 15(1), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010032 - 27 Dec 2021
Viewed by 344
Abstract
Influenza viruses provide a great threat for the human population, causing highly contagious respiratory infections that can lead to serious clinical complications. There are a limited variety of influenza antivirals, and these antivirals are subjected to the constant emergence of resistances. Therefore, the [...] Read more.
Influenza viruses provide a great threat for the human population, causing highly contagious respiratory infections that can lead to serious clinical complications. There are a limited variety of influenza antivirals, and these antivirals are subjected to the constant emergence of resistances. Therefore, the development of new antiviral strategies to combat influenza viruses and other RNA viruses must be promoted. In this work, we design a proof-of-concept of a recently described CRISPR/Cas tool that has been proposed as a possible future RNA virus antiviral, named CRISPR/CasRx. For this, we verified the efficiency of the CasRx endonuclease in the degradation of the eGFP mRNA reporter gene and we established the best conditions for, and the efficient performance of, the CRISPR/CasRx system. The results were measured by fluorescence microscopy, flow cytometry, and qRT-PCR. The analyses demonstrated a reduction in fluorescence, regardless of the amount of eGFP reporter plasmid transfected. The analyses showed an 86–90% reduction in fluorescence by flow cytometry and a 51–80% reduction in mRNA expression by qRT-PCR. Our results demonstrate that the CasRx endonuclease is an efficient tool for eGFP mRNA knockdown. Therefore, subsequent experiments could be useful for the development of a new antiviral tool. Full article
(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)
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Article
Antiviral Activity of Isoquinolone Derivatives against Influenza Viruses and Their Cytotoxicity
Pharmaceuticals 2021, 14(7), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070650 - 06 Jul 2021
Viewed by 817
Abstract
Influenza viruses are one of the major causative agents for human respiratory infections. Currently, vaccines and antivirals approved for preventing and treating viral infections are available. However, limited protection efficacy and frequent emergence of drug-resistant viruses stand for a need for the development [...] Read more.
Influenza viruses are one of the major causative agents for human respiratory infections. Currently, vaccines and antivirals approved for preventing and treating viral infections are available. However, limited protection efficacy and frequent emergence of drug-resistant viruses stand for a need for the development of antivirals with different chemical skeletons from existing drugs. Screening of a chemical library identified an isoquinolone compound (1) as a hit with 50% effective concentrations (EC50s) between 0.2 and 0.6 µM against the influenza A and B viruses. However, it exhibited severe cytotoxic effects with a 50% cytotoxic concentration (CC50) of 39.0 µM in canine kidney epithelial cells. To address this cytotoxic issue, we synthesized an additional 22 chemical derivatives. Through structure-activity, as well as structure-cytotoxicity relationship studies, we discovered compound 21 that has higher EC50 values ranging from 9.9 to 18.5 µM, but greatly alleviated cytotoxicity with a CC50 value over 300 µM. Mode-of-action and cell type-dependent antiviral experiments indicated that it targets viral polymerase activity and functions also in human cells. Here, we present a new class of viral polymerase inhibitors with a core skeleton of isoquinolone, of which antiviral activity could be better improved through following design and synthesis of its derivatives for drug development. Full article
(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)
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Review

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Review
Small Molecule Inhibitors of Influenza Virus Entry
Pharmaceuticals 2021, 14(6), 587; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060587 - 18 Jun 2021
Cited by 1 | Viewed by 934
Abstract
Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its [...] Read more.
Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs. Full article
(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)
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Review
The Antiviral Role of Galectins toward Influenza A Virus Infection—An Alternative Strategy for Influenza Therapy
Pharmaceuticals 2021, 14(5), 490; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050490 - 20 May 2021
Viewed by 1123
Abstract
Animal lectins are proteins with carbohydrate recognition activity. Galectins, the β-galactoside binding lectins, are expressed in various cells and have been reported to regulate several immunological and physiological responses. Recently, some galectins have been reported to regulate some viral infections, including influenza A [...] Read more.
Animal lectins are proteins with carbohydrate recognition activity. Galectins, the β-galactoside binding lectins, are expressed in various cells and have been reported to regulate several immunological and physiological responses. Recently, some galectins have been reported to regulate some viral infections, including influenza A virus (IAV); however, the mechanism is still not fully understood. Thus, we aim to review systemically the roles of galectins in their antiviral functions against IAVs. The PRISMA guidelines were used to select the eligible articles. Results indicated that only Galectin-1, Galectin-3, and Galectin-9 were reported to play a regulatory role in IAV infection. These regulatory effects occur extracellularly, through their carbohydrate recognition domain (CRD) interacting with glycans expressed on the virus surface, as well as endogenously, in a cell–cell interaction manner. The inhibition effects induced by galectins on IAV infection were through blocking virus–host receptors interaction, activation of NLRP-3 inflammasome, augment expression of antiviral genes and related cytokines, as well as stimulation of Tim-3 related signaling to enhance virus-specific T cells and humoral immune response. Combined, this study concludes that currently, only three galectins have reported antiviral capabilities against IAV infection, thereby having the potential to be applied as an alternative anti-influenza therapeutic strategy. Full article
(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)
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