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Identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.

Identifieur interne : 000461 ( PubMed/Checkpoint ); précédent : 000460; suivant : 000462

Identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.

Auteurs : Young Sup Shin [Corée du Sud] ; Dnyandev B. Jarhad [Corée du Sud] ; Min Hwan Jang [Corée du Sud] ; Kristina Kovacikova [Pays-Bas] ; Gyudong Kim [Corée du Sud] ; Ji-Seong Yoon [Corée du Sud] ; Hong-Rae Kim [Corée du Sud] ; Young Eum Hyun [Corée du Sud] ; Amol S. Tipnis [Corée du Sud] ; Tong-Shin Chang [Corée du Sud] ; Martijn J. Van Hemert [Pays-Bas] ; Lak Shin Jeong [Corée du Sud]

Source :

European journal of medicinal chemistry [ 1768-3254 ] ; 2020.

RBID : pubmed:31841728

Descripteurs français

KwdFr :
- Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cristallographie aux rayons X, Modèles moléculaires, Relation dose-effet des médicaments, Relation structure-activité, Réplication virale (), Structure moléculaire, Tests de sensibilité microbienne, Virus du chikungunya ().
MESH :
- pharmacologie : Antiviraux.
- synthèse chimique : Antiviraux.
- Antiviraux, Cristallographie aux rayons X, Modèles moléculaires, Relation dose-effet des médicaments, Relation structure-activité, Réplication virale, Structure moléculaire, Tests de sensibilité microbienne, Virus du chikungunya.

English descriptors

KwdEn :
- Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Chikungunya virus (drug effects), Crystallography, X-Ray, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Virus Replication (drug effects).
MESH :
- chemical , chemical synthesis : Antiviral Agents.
- chemical , chemistry : Antiviral Agents.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Chikungunya virus, Virus Replication.
- Crystallography, X-Ray, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship.

Abstract

We have reported on aristeromycin (1) and 6'-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5'-phosphorylation, we designed and synthesized one-carbon homologated 6'-fluorinated-aristeromycin analogues. This modification prevents 5'-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-l-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6'-fluorinated-5'-homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6'-β-fluoroadenosine analogue 3a was the most potent (IC₅₀ = 0.36 μM). Among the compounds tested, 6'-β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC₅₀ = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC₅₀ values (0.36 and 0.37 μM, respectively), which suggested that 3a's antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6'-β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years.

DOI: 10.1016/j.ejmech.2019.111956
PubMed: 31841728

Affiliations:

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<term>Chikungunya virus (drug effects)</term>
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<term>Dose-Response Relationship, Drug</term>
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<term>Modèles moléculaires</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Structure moléculaire</term>
<term>Tests de sensibilité microbienne</term>
<term>Virus du chikungunya ()</term>
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<term>Virus Replication</term>
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<front><div type="abstract" xml:lang="en">We have reported on aristeromycin (1) and 6'-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5'-phosphorylation, we designed and synthesized one-carbon homologated 6'-fluorinated-aristeromycin analogues. This modification prevents 5'-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-l-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6'-fluorinated-5'-homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6'-β-fluoroadenosine analogue 3a was the most potent (IC<sub>50</sub>
 = 0.36 μM). Among the compounds tested, 6'-β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC<sub>50</sub>
 = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC<sub>50</sub>
 values (0.36 and 0.37 μM, respectively), which suggested that 3a's antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6'-β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31841728</PMID>
<DateCompleted><Year>2020</Year>
<Month>03</Month>
<Day>10</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>04</Month>
<Day>07</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1768-3254</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>187</Volume>
<PubDate><Year>2020</Year>
<Month>Feb</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>European journal of medicinal chemistry</Title>
<ISOAbbreviation>Eur J Med Chem</ISOAbbreviation>
</Journal>
<ArticleTitle>Identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.</ArticleTitle>
<Pagination><MedlinePgn>111956</MedlinePgn>
</Pagination>
<ELocationID EIdType="pii" ValidYN="Y">S0223-5234(19)31108-0</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejmech.2019.111956</ELocationID>
<Abstract><AbstractText>We have reported on aristeromycin (1) and 6'-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5'-phosphorylation, we designed and synthesized one-carbon homologated 6'-fluorinated-aristeromycin analogues. This modification prevents 5'-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-l-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6'-fluorinated-5'-homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6'-β-fluoroadenosine analogue 3a was the most potent (IC<sub>50</sub>
 = 0.36 μM). Among the compounds tested, 6'-β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC<sub>50</sub>
 = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC<sub>50</sub>
 values (0.36 and 0.37 μM, respectively), which suggested that 3a's antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6'-β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years.</AbstractText>
<CopyrightInformation>Copyright © 2019 Elsevier Masson SAS. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Shin</LastName>
<ForeName>Young Sup</ForeName>
<Initials>YS</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jarhad</LastName>
<ForeName>Dnyandev B</ForeName>
<Initials>DB</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jang</LastName>
<ForeName>Min Hwan</ForeName>
<Initials>MH</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kovacikova</LastName>
<ForeName>Kristina</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Gyudong</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yoon</LastName>
<ForeName>Ji-Seong</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Hong-Rae</ForeName>
<Initials>HR</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hyun</LastName>
<ForeName>Young Eum</ForeName>
<Initials>YE</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tipnis</LastName>
<ForeName>Amol S</ForeName>
<Initials>AS</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chang</LastName>
<ForeName>Tong-Shin</ForeName>
<Initials>TS</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>van Hemert</LastName>
<ForeName>Martijn J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jeong</LastName>
<ForeName>Lak Shin</ForeName>
<Initials>LS</Initials>
<AffiliationInfo><Affiliation>Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea. Electronic address: lakjeong@snu.ac.kr.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2019</Year>
<Month>12</Month>
<Day>09</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>France</Country>
<MedlineTA>Eur J Med Chem</MedlineTA>
<NlmUniqueID>0420510</NlmUniqueID>
<ISSNLinking>0223-5234</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002646" MajorTopicYN="N">Chikungunya virus</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004305" MajorTopicYN="N">Dose-Response Relationship, Drug</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008826" MajorTopicYN="N">Microbial Sensitivity Tests</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">6′-fluorohomoaristeromycin</Keyword>
<Keyword MajorTopicYN="N">Anti-RNA virus</Keyword>
<Keyword MajorTopicYN="N">Chikungunya</Keyword>
<Keyword MajorTopicYN="N">Electrophilic fluorination</Keyword>
<Keyword MajorTopicYN="N">S-adenosylhomocysteine hydrolase</Keyword>
</KeywordList>
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<Month>11</Month>
<Day>05</Day>
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<Month>12</Month>
<Day>06</Day>
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<Month>12</Month>
<Day>17</Day>
<Hour>6</Hour>
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<Day>11</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
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<tree><country name="Corée du Sud"><noRegion><name sortKey="Shin, Young Sup" sort="Shin, Young Sup" uniqKey="Shin Y" first="Young Sup" last="Shin">Young Sup Shin</name>
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Identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.

Identification of 6'-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication.

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