GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition.
Identifieur interne : 000A42 ( Main/Corpus ); précédent : 000A41; suivant : 000A43GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition.
Auteurs : Philippe Halfon ; Eloïne Bestion ; Keivan Zandi ; Julien Andreani ; Jean-Pierre Baudoin ; Bernard La Scola ; Jean-Louis Mege ; Soraya Mezouar ; Raymond F. SchinaziSource :
- bioRxiv : the preprint server for biology ; 2020.
Abstract
Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection.
DOI: 10.1101/2020.10.06.327635
PubMed: 33052342
PubMed Central: PMC7553169
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Schinazi</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:33052342</idno><idno type="pmid">33052342</idno><idno type="doi">10.1101/2020.10.06.327635</idno><idno type="pmc">PMC7553169</idno><idno type="wicri:Area/Main/Corpus">000A42</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000A42</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">GNS561 exhibits potent <i>in vitro</i> antiviral activity against SARS-CoV-2 through autophagy inhibition.</title><author><name sortKey="Halfon, Philippe" sort="Halfon, Philippe" uniqKey="Halfon P" first="Philippe" last="Halfon">Philippe Halfon</name></author><author><name sortKey="Bestion, Eloine" sort="Bestion, Eloine" uniqKey="Bestion E" first="Eloïne" last="Bestion">Eloïne Bestion</name></author><author><name sortKey="Zandi, Keivan" sort="Zandi, Keivan" uniqKey="Zandi K" first="Keivan" last="Zandi">Keivan Zandi</name></author><author><name sortKey="Andreani, Julien" sort="Andreani, Julien" uniqKey="Andreani J" first="Julien" last="Andreani">Julien Andreani</name></author><author><name sortKey="Baudoin, Jean Pierre" sort="Baudoin, Jean Pierre" uniqKey="Baudoin J" first="Jean-Pierre" last="Baudoin">Jean-Pierre Baudoin</name></author><author><name sortKey="La Scola, Bernard" sort="La Scola, Bernard" uniqKey="La Scola B" first="Bernard" last="La Scola">Bernard La Scola</name></author><author><name sortKey="Mege, Jean Louis" sort="Mege, Jean Louis" uniqKey="Mege J" first="Jean-Louis" last="Mege">Jean-Louis Mege</name></author><author><name sortKey="Mezouar, Soraya" sort="Mezouar, Soraya" uniqKey="Mezouar S" first="Soraya" last="Mezouar">Soraya Mezouar</name></author><author><name sortKey="Schinazi, Raymond F" sort="Schinazi, Raymond F" uniqKey="Schinazi R" first="Raymond F" last="Schinazi">Raymond F. Schinazi</name></author></analytic><series><title level="j">bioRxiv : the preprint server for biology</title><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">33052342</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>15</Day></DateRevised><Article PubModel="Electronic"><Journal><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Oct</Month><Day>06</Day></PubDate></JournalIssue><Title>bioRxiv : the preprint server for biology</Title><ISOAbbreviation>bioRxiv</ISOAbbreviation></Journal><ArticleTitle>GNS561 exhibits potent <i>in vitro</i> antiviral activity against SARS-CoV-2 through autophagy inhibition.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">2020.10.06.327635</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1101/2020.10.06.327635</ELocationID><Abstract><AbstractText>Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Halfon</LastName><ForeName>Philippe</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Bestion</LastName><ForeName>Eloïne</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Zandi</LastName><ForeName>Keivan</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Andreani</LastName><ForeName>Julien</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Baudoin</LastName><ForeName>Jean-Pierre</ForeName><Initials>JP</Initials></Author><Author ValidYN="Y"><LastName>La Scola</LastName><ForeName>Bernard</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Mege</LastName><ForeName>Jean-Louis</ForeName><Initials>JL</Initials></Author><Author ValidYN="Y"><LastName>Mezouar</LastName><ForeName>Soraya</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Schinazi</LastName><ForeName>Raymond F</ForeName><Initials>RF</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D000076942">Preprint</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>10</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>bioRxiv</MedlineTA><NlmUniqueID>101680187</NlmUniqueID></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>10</Month><Day>14</Day><Hour>12</Hour><Minute>44</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>10</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>10</Month><Day>15</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">33052342</ArticleId><ArticleId IdType="doi">10.1101/2020.10.06.327635</ArticleId><ArticleId IdType="pmc">PMC7553169</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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