tetano
Editor, Senior Moderator
J Med Virol
. 2020 Oct 7.
doi: 10.1002/jmv.26583. Online ahead of print.
Suppression of SARS-CoV-2 infection in ex-vivo human lung tissues by targeting class III phosphoinositide 3-kinase
Chun-Kit Yuen[SUP] 1 [/SUP], Wan-Man Wong[SUP] 1 [/SUP], Long-Fung Mak[SUP] 1 [/SUP], Xiaohui Wang[SUP] 1 [/SUP], Hin Chu[SUP] 1 [/SUP], Kwok-Yung Yuen[SUP] 1 [/SUP], Kin-Hang Kok[SUP] 1 [/SUP]
Affiliations
Abstract
The novel betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged at the end of 2019 and caused the Coronavirus disease 19 (COVID-19) pandemic due to its high transmissibility and early immunosuppression. Previous studies on other betacoronaviruses suggested that betacoronavirus infection is associated with the host autophagy pathway. However, it is unclear whether any components of autophagy, or virophagy, can be the therapeutic targets for COVID-19 treatment. In this report, we examined the antiviral effect of four well-characterized small molecule inhibitors that target the key cellular factors involved in key steps of the autophagy pathway. They includes small molecules targeting the ULK1/Atg1 complex involved in the induction stage of autophagy (ULK1 inhibitor SBI0206965), the ATG14/Beclin1/VPS34 complex involved in the nucleation step of autophagy (class III PI3-kinase inhibitor VPS34-IN1), plus a widely-used autophagy inhibitor that persistently inhibiting class I and temporary inhibiting class III PI3-kinase (3-MA) and a clinically approved autophagy inhibitor that suppresses autophagy by inhibiting lysosomal acidification and prevents the formation of autophagolysosome (HCQ). Surprisingly, not all the tested autophagy inhibitors suppressed SARS-CoV-2 infection. We showed that inhibition of the class III PI3-kinase involved in the initiation step of both canonical and non-canonical autophagy potently suppressed SARS-CoV-2 at nano-molar level. In addition, this specific kinase inhibitor VPS34-IN1, and its bioavailable analogue VVPS34-IN1, potently inhibited SARS-CoV-2 infection in ex-vivo human lung tissues. Taken together, class III PI3-kinase may be a possible target for COVID-19 therapeutics development. This article is protected by copyright. All rights reserved.
Keywords: COVID-19; Class III PI3-K; SARS-CoV-2; Vps34; ex-vivo human lung tissues.
. 2020 Oct 7.
doi: 10.1002/jmv.26583. Online ahead of print.
Suppression of SARS-CoV-2 infection in ex-vivo human lung tissues by targeting class III phosphoinositide 3-kinase
Chun-Kit Yuen[SUP] 1 [/SUP], Wan-Man Wong[SUP] 1 [/SUP], Long-Fung Mak[SUP] 1 [/SUP], Xiaohui Wang[SUP] 1 [/SUP], Hin Chu[SUP] 1 [/SUP], Kwok-Yung Yuen[SUP] 1 [/SUP], Kin-Hang Kok[SUP] 1 [/SUP]
Affiliations
- PMID: 33026649
- DOI: 10.1002/jmv.26583
Abstract
The novel betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged at the end of 2019 and caused the Coronavirus disease 19 (COVID-19) pandemic due to its high transmissibility and early immunosuppression. Previous studies on other betacoronaviruses suggested that betacoronavirus infection is associated with the host autophagy pathway. However, it is unclear whether any components of autophagy, or virophagy, can be the therapeutic targets for COVID-19 treatment. In this report, we examined the antiviral effect of four well-characterized small molecule inhibitors that target the key cellular factors involved in key steps of the autophagy pathway. They includes small molecules targeting the ULK1/Atg1 complex involved in the induction stage of autophagy (ULK1 inhibitor SBI0206965), the ATG14/Beclin1/VPS34 complex involved in the nucleation step of autophagy (class III PI3-kinase inhibitor VPS34-IN1), plus a widely-used autophagy inhibitor that persistently inhibiting class I and temporary inhibiting class III PI3-kinase (3-MA) and a clinically approved autophagy inhibitor that suppresses autophagy by inhibiting lysosomal acidification and prevents the formation of autophagolysosome (HCQ). Surprisingly, not all the tested autophagy inhibitors suppressed SARS-CoV-2 infection. We showed that inhibition of the class III PI3-kinase involved in the initiation step of both canonical and non-canonical autophagy potently suppressed SARS-CoV-2 at nano-molar level. In addition, this specific kinase inhibitor VPS34-IN1, and its bioavailable analogue VVPS34-IN1, potently inhibited SARS-CoV-2 infection in ex-vivo human lung tissues. Taken together, class III PI3-kinase may be a possible target for COVID-19 therapeutics development. This article is protected by copyright. All rights reserved.
Keywords: COVID-19; Class III PI3-K; SARS-CoV-2; Vps34; ex-vivo human lung tissues.