Research

13 pages, 3287 KiB

Open AccessArticle

Antigenic Characterization of Neuraminidase of Influenza A/H7N9 Viruses Isolated in Different Years

by Yulia Desheva, Igor Losev, Nadezhda Petkova, Polina Kudar, Svetlana Donina, Andrey Mamontov, Chih-Hsuan Tsai and Yu-Chan Chao

Pharmaceuticals 2022, 15(9), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091127 - 09 Sep 2022

Cited by 2 | Viewed by 1813

Abstract

Influenza outbreaks caused by A/H7N9 viruses have occurred since 2013. After 2016, A/H7N9 influenza viruses underwent evolutionary changes. In this study, we examined the antigenic properties of influenza neuraminidase (NA) of A/H7N9 viruses as part of a live influenza vaccine (LAIV). It was [...] Read more.

Influenza outbreaks caused by A/H7N9 viruses have occurred since 2013. After 2016, A/H7N9 influenza viruses underwent evolutionary changes. In this study, we examined the antigenic properties of influenza neuraminidase (NA) of A/H7N9 viruses as part of a live influenza vaccine (LAIV). It was shown that neuraminidase inhibiting (NI) antibodies obtained after A/Anhui/1/2013(H7N9)-based LAIV vaccination did not inhibit A/Hong Kong/125/2017(H7N9) NA and vice versa. The A/Hong Kong/125/2017(H7N9)-based LAIV elicited higher levels of NI antibodies compared to the A/Anhui/1/2013(H7N9)-based LAIV after two doses. Thelow degree of coincidence of the antibody response to hemagglutinin (HA) and NA after LAIV vaccination allows us to consider an enzyme-linked lectin assay (ELLA) as an additional measure for assessing the immunogenicity of influenza vaccines. In mice, N9-reactive monoclonal antibodies (mABs) for the A/environment/Shanghai/RL01/2013(H7N9) influenza virus partially protected against lung infection from the A/Guangdong/17SF003/2016 IDCDC-RG56N(H7N9) virus, thus showing the cross-protective properties of monoclonal antibodies against the drift variant. Full article

(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)

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13 pages, 1744 KiB

Open AccessArticle

Study of Antibodies to Influenza Neuraminidase N2

by Yulia Desheva, Nadezhda Petkova, Tatiana Smolonogina, Svetlana Donina and Alexey Go

Pharmaceuticals 2022, 15(5), 498; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050498 - 19 Apr 2022

Viewed by 1531

Abstract

Humoral immunity to influenza neuraminidase (NA) was evaluated among different groups of people including patients with acute influenza infection and healthy people in different age groups using an enzyme linked lectin assay (ELLA). The amino acid composition of NA of seasonal influenza viruses [...] Read more.

Humoral immunity to influenza neuraminidase (NA) was evaluated among different groups of people including patients with acute influenza infection and healthy people in different age groups using an enzyme linked lectin assay (ELLA). The amino acid composition of NA of seasonal influenza viruses A/Victoria/361/2011(H3N2) and A/Hong Kong/4801/2014(H3N2) differed by 2%, while cross-reacting neuraminidase-inhibiting (NI) antibodies to them in the same serum samples were detected in 10% of cases. Middle-aged patients born from 1977 to 2000 had a high level of hemagglutination-inhibiting (HI) antibodies to A/Hong Kong/4801/2014(H3N2), but almost no NI antibodies, which may indicate that in the case of a change in the hemagglutinin (HA) subtype, this age group will be susceptible to influenza A/H3N2 viruses. Therefore, it could mean there is a need for priority vaccination of this age group with a vaccine against the appropriate strain. It was shown that after intranasal administration of live influenza vaccine (LAIV) for the 2017–2018 season, serum antibody response was not lower compared to that during natural infection. In older people, antibodies to archival A/H2N2 viruses were detected more often than to modern A/H3N2. Since the conversion of antibodies to HA and NA often did not coincide, antibodies to NA can serve as an additional criterion for assessing the immunogenicity of influenza vaccines. Full article

(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)

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19 pages, 34041 KiB

Open AccessArticle

Broad-Spectrum Activity of Small Molecules Acting against Influenza a Virus: Biological and Computational Studies

by Mariangela Agamennone and Fabiana Superti

Pharmaceuticals 2022, 15(3), 301; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030301 - 28 Feb 2022

Cited by 3 | Viewed by 2205

Abstract

Influenza still represents a problematic disease, involving millions of people every year and causing hundreds of thousands of deaths. Only a few drugs are clinically available. The search for an effective weapon is still ongoing. In this scenario, we recently identified new drug-like [...] Read more.

Influenza still represents a problematic disease, involving millions of people every year and causing hundreds of thousands of deaths. Only a few drugs are clinically available. The search for an effective weapon is still ongoing. In this scenario, we recently identified new drug-like compounds with antiviral activity toward two A/H1N1 Influenza virus strains, which were demonstrated to interfere with the processes mediated by hemagglutinin (HA). In the present work, the compound’s ability to act against the A/H3N2 viral strain has been evaluated in hemagglutination inhibition (HI) assays. Two of the five tested compounds were also active toward the A/H3N2 Influenza virus. To validate the scaffold activity, analogue compounds of two broad-spectrum molecules were selected and purchased for HI testing on both A/H1N1 and A/H3N2 Influenza viruses. Forty-three compounds were tested, and four proved to be active toward all three viral strains. A computational study has been carried out to depict the HA binding process of the most interesting compounds. Full article

(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)

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11 pages, 2319 KiB

Open AccessArticle

CRISPR/CasRx Proof-of-Concept for RNA Degradation: A Future Tool against RNA Viruses?

by Diana Perez-SanJose, Miguel Angel de la Fuente, Julia Serna Pérez, Maria Simarro, José María Eiros Bouza and Ivan Sanz-Muñoz

Pharmaceuticals 2022, 15(1), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010032 - 27 Dec 2021

Cited by 1 | Viewed by 2873

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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14 pages, 2667 KiB

Open AccessArticle

Antiviral Activity of Isoquinolone Derivatives against Influenza Viruses and Their Cytotoxicity

by Yejin Jang, Jinhe Han, Xiaoli Li, Hyunjin Shin, Won-Jea Cho and Meehyein Kim

Pharmaceuticals 2021, 14(7), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070650 - 06 Jul 2021

Cited by 6 | Viewed by 2112

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

Jump to: Research, Other

19 pages, 4630 KiB

Open AccessReview

Small Molecule Inhibitors of Influenza Virus Entry

by Zhaoyu Chen, Qinghua Cui, Michael Caffrey, Lijun Rong and Ruikun Du

Pharmaceuticals 2021, 14(6), 587; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060587 - 18 Jun 2021

Cited by 20 | Viewed by 4190

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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15 pages, 2062 KiB

Open AccessReview

The Antiviral Role of Galectins toward Influenza A Virus Infection—An Alternative Strategy for Influenza Therapy

by Chih-Yen Lin, Zih-Syuan Yang, Wen-Hung Wang, Aspiro Nayim Urbina, Yu-Ting Lin, Jason C. Huang, Fu-Tong Liu and Sheng-Fan Wang

Pharmaceuticals 2021, 14(5), 490; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050490 - 20 May 2021

Cited by 5 | Viewed by 3137

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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Other

Jump to: Research, Review

11 pages, 1167 KiB

Open AccessCase Report

Successful Treatment of Complicated Influenza A(H3N2) Virus Infection and Rhabdomyolysis with Compassionate Use of IV Zanamivir

by Maren Alchikh, Patrick E. Obermeier, Brunhilde Schweiger and Barbara A. Rath

Pharmaceuticals 2023, 16(1), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010085 - 07 Jan 2023

Cited by 1 | Viewed by 3111

Abstract

In 2019, EMA licensed intravenous (IV) zanamivir for severe influenza virus infection in children over 6 months as well as adults. Prior to that, it was possible via a compassionate use program. We present successful compassionate use of IV zanamivir in a 14-year-old [...] Read more.

In 2019, EMA licensed intravenous (IV) zanamivir for severe influenza virus infection in children over 6 months as well as adults. Prior to that, it was possible via a compassionate use program. We present successful compassionate use of IV zanamivir in a 14-year-old female with severe influenza A(H3N2) and multi-organ failure, who had failed oral oseltamivir. Her illness was complicated by acute respiratory distress syndrome and rhabdomyolysis requiring extracorporeal membrane oxygenation and hemofiltration. Considering the broad safety margins with neuraminidase inhibitors, an adult dose of 600 mg IV BID was administered in this 60 kg patient. Influenza virus was cleared rapidly and undetectable on day 13. Creatine kinase (CK) values were dropping from 38,000 to 500 within nine days. Given the recent licensure of IV zanamivir, multi-center prospective observational studies in pediatric Intensive Care Unit patients would be beneficial to guide the most appropriate use of IV zanamivir in this vulnerable age group. Full article

(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)

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