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Article: Suppression of SARS‐CoV‐2 infection in ex‐vivo human lung tissues by targeting class III phosphoinositide 3‐kinase

TitleSuppression of SARS‐CoV‐2 infection in ex‐vivo human lung tissues by targeting class III phosphoinositide 3‐kinase
Authors
KeywordsCOVID-19
SARS-CoV-2
Vps34
class III PI3-K
ex vivo human lung tissues
Issue Date2021
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/32763
Citation
Journal of Medical Virology, 2021, v. 93 n. 4, p. 2076-2083 How to Cite?
AbstractThe novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 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 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 include 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), and a widely-used autophagy inhibitor that persistently inhibits class I and temporary inhibits 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 class III PI3-kinase involved in the initiation step of both canonical and noncanonical autophagy potently suppressed SARS-CoV-2 at a 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 therapeutic development.
Persistent Identifierhttp://hdl.handle.net/10722/305003
ISSN
2020 Impact Factor: 2.327
2020 SCImago Journal Rankings: 0.782
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuen, CK-
dc.contributor.authorWong, WM-
dc.contributor.authorMak, LF-
dc.contributor.authorWang, X-
dc.contributor.authorChu, H-
dc.contributor.authorYuen, KY-
dc.contributor.authorKok, KH-
dc.date.accessioned2021-10-05T02:38:21Z-
dc.date.available2021-10-05T02:38:21Z-
dc.date.issued2021-
dc.identifier.citationJournal of Medical Virology, 2021, v. 93 n. 4, p. 2076-2083-
dc.identifier.issn0146-6615-
dc.identifier.urihttp://hdl.handle.net/10722/305003-
dc.description.abstractThe novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 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 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 include 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), and a widely-used autophagy inhibitor that persistently inhibits class I and temporary inhibits 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 class III PI3-kinase involved in the initiation step of both canonical and noncanonical autophagy potently suppressed SARS-CoV-2 at a 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 therapeutic development.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/32763-
dc.relation.ispartofJournal of Medical Virology-
dc.rightsSubmitted (preprint) Version This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Accepted (peer-reviewed) Version This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectCOVID-19-
dc.subjectSARS-CoV-2-
dc.subjectVps34-
dc.subjectclass III PI3-K-
dc.subjectex vivo human lung tissues-
dc.titleSuppression of SARS‐CoV‐2 infection in ex‐vivo human lung tissues by targeting class III phosphoinositide 3‐kinase-
dc.typeArticle-
dc.identifier.emailYuen, CK: jackyuen@connect.hku.hk-
dc.identifier.emailWong, WM: louisewong@hku.hk-
dc.identifier.emailMak, LF: maxmak91@hku.hk-
dc.identifier.emailWang, X: xiaohuiwang@hku.hk-
dc.identifier.emailChu, H: hinchu@hku.hk-
dc.identifier.emailYuen, KY: kyyuen@hkucc.hku.hk-
dc.identifier.emailKok, KH: khkok@hku.hk-
dc.identifier.authorityWang, X=rp02664-
dc.identifier.authorityChu, H=rp02125-
dc.identifier.authorityYuen, KY=rp00366-
dc.identifier.authorityKok, KH=rp01455-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1002/jmv.26583-
dc.identifier.pmid33026649-
dc.identifier.pmcidPMC7675438-
dc.identifier.scopuseid_2-s2.0-85094203168-
dc.identifier.hkuros326087-
dc.identifier.volume93-
dc.identifier.issue4-
dc.identifier.spage2076-
dc.identifier.epage2083-
dc.identifier.isiWOS:000585064800001-
dc.publisher.placeUnited States-

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