Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.
Identifieur interne : 000195 ( PubMed/Corpus ); précédent : 000194; suivant : 000196Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.
Auteurs : Mahmoud Kandeel ; Mizuki Yamamoto ; Abdulla Al-Taher ; Aya Watanabe ; Kentaro Oh-Hashi ; Byoung Kwon Park ; Hyung-Joo Kwon ; Jun-Ichiro Inoue ; Mohammed Al-NazawiSource :
- Biomolecules & therapeutics [ 1976-9148 ] ; 2020.
Abstract
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC50 values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 (HEK293) at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.
DOI: 10.4062/biomolther.2019.202
PubMed: 32126736
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Al-Taher</name><affiliation><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation></affiliation></author><author><name sortKey="Watanabe, Aya" sort="Watanabe, Aya" uniqKey="Watanabe A" first="Aya" last="Watanabe">Aya Watanabe</name><affiliation><nlm:affiliation>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Oh Hashi, Kentaro" sort="Oh Hashi, Kentaro" uniqKey="Oh Hashi K" first="Kentaro" last="Oh-Hashi">Kentaro Oh-Hashi</name><affiliation><nlm:affiliation>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Park, Byoung Kwon" sort="Park, Byoung Kwon" uniqKey="Park B" first="Byoung Kwon" last="Park">Byoung Kwon Park</name><affiliation><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation></affiliation></author><author><name sortKey="Kwon, Hyung Joo" sort="Kwon, Hyung Joo" uniqKey="Kwon H" first="Hyung-Joo" last="Kwon">Hyung-Joo Kwon</name><affiliation><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation></affiliation></author><author><name sortKey="Inoue, Jun Ichiro" sort="Inoue, Jun Ichiro" uniqKey="Inoue J" first="Jun-Ichiro" last="Inoue">Jun-Ichiro Inoue</name><affiliation><nlm:affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Al Nazawi, Mohammed" sort="Al Nazawi, Mohammed" uniqKey="Al Nazawi M" first="Mohammed" last="Al-Nazawi">Mohammed Al-Nazawi</name><affiliation><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32126736</idno><idno type="pmid">32126736</idno><idno type="doi">10.4062/biomolther.2019.202</idno><idno type="wicri:Area/PubMed/Corpus">000195</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000195</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.</title><author><name sortKey="Kandeel, Mahmoud" sort="Kandeel, Mahmoud" uniqKey="Kandeel M" first="Mahmoud" last="Kandeel">Mahmoud Kandeel</name><affiliation><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation></affiliation></author><author><name sortKey="Yamamoto, Mizuki" sort="Yamamoto, Mizuki" uniqKey="Yamamoto M" first="Mizuki" last="Yamamoto">Mizuki Yamamoto</name><affiliation><nlm:affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Al Taher, Abdulla" sort="Al Taher, Abdulla" uniqKey="Al Taher A" first="Abdulla" last="Al-Taher">Abdulla Al-Taher</name><affiliation><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation></affiliation></author><author><name sortKey="Watanabe, Aya" sort="Watanabe, Aya" uniqKey="Watanabe A" first="Aya" last="Watanabe">Aya Watanabe</name><affiliation><nlm:affiliation>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Oh Hashi, Kentaro" sort="Oh Hashi, Kentaro" uniqKey="Oh Hashi K" first="Kentaro" last="Oh-Hashi">Kentaro Oh-Hashi</name><affiliation><nlm:affiliation>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Park, Byoung Kwon" sort="Park, Byoung Kwon" uniqKey="Park B" first="Byoung Kwon" last="Park">Byoung Kwon Park</name><affiliation><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation></affiliation></author><author><name sortKey="Kwon, Hyung Joo" sort="Kwon, Hyung Joo" uniqKey="Kwon H" first="Hyung-Joo" last="Kwon">Hyung-Joo Kwon</name><affiliation><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation></affiliation></author><author><name sortKey="Inoue, Jun Ichiro" sort="Inoue, Jun Ichiro" uniqKey="Inoue J" first="Jun-Ichiro" last="Inoue">Jun-Ichiro Inoue</name><affiliation><nlm:affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Al Nazawi, Mohammed" sort="Al Nazawi, Mohammed" uniqKey="Al Nazawi M" first="Mohammed" last="Al-Nazawi">Mohammed Al-Nazawi</name><affiliation><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Biomolecules & therapeutics</title><idno type="ISSN">1976-9148</idno><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">Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC<sub>50</sub> values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 (HEK293) at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32126736</PMID><DateRevised><Year>2020</Year><Month>03</Month><Day>04</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">1976-9148</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2020</Year><Month>Mar</Month><Day>04</Day></PubDate></JournalIssue><Title>Biomolecules & therapeutics</Title><ISOAbbreviation>Biomol Ther (Seoul)</ISOAbbreviation></Journal><ArticleTitle>Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.</ArticleTitle><ELocationID EIdType="doi" ValidYN="Y">10.4062/biomolther.2019.202</ELocationID><Abstract><AbstractText>Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC<sub>50</sub> values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 (HEK293) at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kandeel</LastName><ForeName>Mahmoud</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yamamoto</LastName><ForeName>Mizuki</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Al-Taher</LastName><ForeName>Abdulla</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Watanabe</LastName><ForeName>Aya</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Oh-Hashi</LastName><ForeName>Kentaro</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Byoung Kwon</ForeName><Initials>BK</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kwon</LastName><ForeName>Hyung-Joo</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Inoue</LastName><ForeName>Jun-Ichiro</ForeName><Initials>JI</Initials><AffiliationInfo><Affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Al-Nazawi</LastName><ForeName>Mohammed</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>03</Month><Day>04</Day></ArticleDate></Article><MedlineJournalInfo><Country>Korea (South)</Country><MedlineTA>Biomol Ther (Seoul)</MedlineTA><NlmUniqueID>101472832</NlmUniqueID><ISSNLinking>1976-9148</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Antiviral agents</Keyword><Keyword MajorTopicYN="N">MERS-CoV</Keyword><Keyword MajorTopicYN="N">Plaques 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