Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets

Imai, Masaki; Yamashita, Makoto; Sakai‐Tagawa, Yuko; Iwatsuki‐Horimoto, Kiyoko; Kiso, Maki; Murakami, Jurika; Yasuhara, Atsuhiro; Takada, Kenjiro; Ito, Mutsumi; Nakajima, N.; Takahashi, Keiichi; Lopes, Tiago J. S.; Dutta, Jayeeta; Khan, Zenab; Kriti, Divya; Bakel, Harm van; Tokita, Akifumi; Hagiwara, Haruhisa; Izumida, Naomi; Kuroki, Haruo; Nishino, Tamon; Wada, Noriyuki; Koga, Michiko; Adachi, Eisuke; Jubishi, Daisuke; Hasegawa, Hideki; Kawaoka, Yoshihiro

doi:10.1038/s41564-019-0609-0

Cited by 108 publications

(100 citation statements)

References 18 publications

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“…In contrast, Checkmahomed et al (2020) reported that the PA I38T substitution did not alter the replication fitness of the contemporary influenza viruses A/Quebec/144147/2009(H1N1)pdm09 and A/Switzerland/9715293/2013(H3N2) in vitro or in mice. Furthermore, A(H1N1)pdm09 and A(H3N2) viruses with the PA I38T substitution isolated from baloxavir-treated patients during the 2018-2019 influenza season showed similar replication fitness and pathogenicity to those of wild-type isolates in hamsters and transmitted efficiently between ferrets by respiratory droplets (Imai et al 2020). These results, together with human-to-human transmission cases in Japan, indicate that currently circulating viruses have already acquired amino acid substitutions to compensate for the fitness costs of the PA I38T substitution.…”

Section: Discussionmentioning

confidence: 99%

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita

2020

Cold Spring Harb Perspect Med

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Section: Discussionmentioning

confidence: 99%

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita

2020

Cold Spring Harb Perspect Med

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“…Concerns about these drugs range from significant side effects to the appearance of drug-resistant viruses after a short period of use. [17] Given the importance of this issue, a number of other antivirals are in clinical trials. [18][19][20][21][22][23][24][25] The majority of these drugs are monoclonal antibodies [26,27] that inhibit the fusion of the virus to the host-cell.…”

mentioning

confidence: 99%

Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

Kocabiyik

Cagno

Silva

et al. 2020

Preprint

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Influenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk of new pandemics remains high and it is likely that the development of a vaccine against strongly virulent influenza strains would take too long, hence would not help the initial fight of the pandemic. Antiviral drugs are available but they are far from ideal. Arguably, the ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6'sialyl-N-acetyllactosamine (6'SLN) or 3'SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. We show that these cyclodextrins are effective against several human or avian influenza strains in vitro, as well as against a 2009 pandemic influenza strain ex vivo and in vivo. Importantly, replacing the hydrophobic linkers with hydrophilic ones results in molecules that are totally ineffective ex vivo, confirming the importance of the virucidal mechanism in the quest of a truly effective antiviral drug.. 1

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“…71,82 However, subsequent followup analyses of the fitness of H1N1 and H3N2 strains containing PA I38 mutants in the ferret model revealed that pathogenesis and transmission success of resistant and the corresponding sensitive viruses were equivalent. 83,84 In mice and ferrets, both loss of animal body weight and lung viral loads were identical after infection with resistant or sensitive viruses, and substitutions at PA I38 remained stable over 4 passages through mice. 85,86 A small percentage of influenza viruses circulating in the United States in the 2016/2017 and 2017/2018 seasons, and thus prior to approval of baloxavir marboxil, contained mutations at PA residue 38.…”

Section: Clinically Used Drugs and Selected Daa Candidates In Advancementioning

confidence: 97%

Next-generation direct-acting influenza therapeutics

Toots

Plemper

2020

Translational Research

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Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.

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Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets

Cited by 108 publications

References 18 publications

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

Next-generation direct-acting influenza therapeutics

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