PMID- 38063402
OWN - NLM
STAT- MEDLINE
DCOM- 20240111
LR  - 20240517
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 68
IP  - 1
DP  - 2024 Jan 10
TI  - Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in 
      human nasal epithelium and mice.
PG  - e0105023
LID - 10.1128/aac.01050-23 [doi]
LID - e01050-23
AB  - Endocytosis, or internalization through endosomes, is a major cell entry 
      mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a 
      critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate 
      (PtdIns (3, 5)P2) and has been implicated in virus trafficking via the endocytic 
      pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and 
      Ebola have been reported, but there is little evidence regarding other 
      respiratory viruses. In this study, we demonstrated the antiviral effects of 
      PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro 
      and in vivo. PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 
      concentration-dependently inhibited several influenza strains in an MDCK 
      cell-cytopathic assay. AM also reduced the viral load and cytokine release, while 
      improving the cell integrity of human nasal air-liquid interface cultured 
      epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when 
      intranasally treated, exhibited a significant reduction of viral load and 
      inflammation and inhibited weight loss caused by influenza infection, with 
      effects being similar to oral oseltamivir (10 mg/kg). In addition, AM 
      demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro 
      and mouse in vivo, with an equivalent effect to that of ribavirin. AM also showed 
      antiviral effects against human rhinovirus and seasonal coronavirus in vitro. 
      Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve 
      inhibitor is a promising molecule for a pan-viral approach against respiratory 
      viruses.
FAU - Baker, Jonathan
AU  - Baker J
AD  - National Heart and Lung Institute, Imperial College , London, United Kingdom.
FAU - Ombredane, Hugo
AU  - Ombredane H
AD  - National Heart and Lung Institute, Imperial College , London, United Kingdom.
FAU - Daly, Leah
AU  - Daly L
AD  - National Heart and Lung Institute, Imperial College , London, United Kingdom.
FAU - Knowles, Ian
AU  - Knowles I
AD  - Pharmidex , London, United Kingdom.
FAU - Rapeport, Garth
AU  - Rapeport G
AD  - National Heart and Lung Institute, Imperial College , London, United Kingdom.
FAU - Ito, Kazuhiro
AU  - Ito K
AUID- ORCID: 0000-0001-9320-2717
AD  - National Heart and Lung Institute, Imperial College , London, United Kingdom.
LA  - eng
GR  - SubIntro Ltd./
PT  - Journal Article
DEP - 20231208
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 20O93L6F9H (Oseltamivir)
RN  - 0 (Antiviral Agents)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Influenza, Human
MH  - Oseltamivir
MH  - *Hemorrhagic Fever, Ebola
MH  - Antiviral Agents/pharmacology/therapeutic use
MH  - Nasal Mucosa
PMC - PMC10777833
OTO - NOTNLM
OT  - Apilimod
OT  - PIKfyve
OT  - air-liquid interface
OT  - coronavirus
OT  - human rhinovirus
OT  - influenza
OT  - respiratory syncytial virus
COIS- J. Baker and H. Ombredane received the research funding from SubIntro Ltd. K. Ito 
      and G. Rapeport were co-founders of SubIntro Ltd. and former consultants of the 
      company. Other authors declare no conflict of interest.
EDAT- 2023/12/08 12:42
MHDA- 2024/01/11 07:42
PMCR- 2024/06/08
CRDT- 2023/12/08 09:03
PHST- 2024/06/08 00:00 [pmc-release]
PHST- 2024/01/11 07:42 [medline]
PHST- 2023/12/08 12:42 [pubmed]
PHST- 2023/12/08 09:03 [entrez]
AID - 01050-23 [pii]
AID - aac.01050-23 [pii]
AID - 10.1128/aac.01050-23 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2024 Jan 10;68(1):e0105023. doi: 
      10.1128/aac.01050-23. Epub 2023 Dec 8.