Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.
Identifieur interne : 000078 ( Main/Exploration ); précédent : 000077; suivant : 000079Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.
Auteurs : Mahmoud Kandeel [Arabie saoudite] ; Mizuki Yamamoto [Japon] ; Abdulla Al-Taher [Arabie saoudite] ; Aya Watanabe [Japon] ; Kentaro Oh-Hashi [Japon] ; Byoung Kwon Park [Corée du Sud] ; Hyung-Joo Kwon [Corée du Sud] ; Jun-Ichiro Inoue [Japon] ; Mohammed Al-Nazawi [Arabie saoudite]Source :
- 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
Affiliations:
- Arabie saoudite, Corée du Sud, Japon
- Préfecture de Gifu, Région de Kantō, Région du Chūbu
- Gifu (ville), Tokyo
- Université de Gifu, Université de Tokyo
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saoudite</country><wicri:regionArea>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982</wicri:regionArea><wicri:noRegion>Al-Ahsa 31982</wicri:noRegion></affiliation></author><author><name sortKey="Yamamoto, Mizuki" sort="Yamamoto, Mizuki" uniqKey="Yamamoto M" first="Mizuki" last="Yamamoto">Mizuki Yamamoto</name><affiliation wicri:level="4"><nlm:affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName><placeName><settlement type="city">Tokyo</settlement><region type="province">Région de Kantō</region></placeName></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 wicri:level="1"><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982</wicri:regionArea><wicri:noRegion>Al-Ahsa 31982</wicri:noRegion></affiliation></author><author><name sortKey="Watanabe, Aya" sort="Watanabe, Aya" uniqKey="Watanabe A" first="Aya" last="Watanabe">Aya Watanabe</name><affiliation wicri:level="4"><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><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName><placeName><settlement type="city">Tokyo</settlement><region type="province">Région de Kantō</region></placeName></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 wicri:level="4"><nlm:affiliation>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193</wicri:regionArea><orgName type="university">Université de Gifu</orgName><placeName><settlement type="city">Gifu (ville)</settlement><region type="province">Région du Chūbu</region><region type="prefecture">Préfecture de Gifu</region></placeName></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 wicri:level="1"><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252</wicri:regionArea><wicri:noRegion>Chuncheon 24252</wicri:noRegion></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 wicri:level="1"><nlm:affiliation>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Microbiology, Hallym University College of Medicine, Chuncheon 24252</wicri:regionArea><wicri:noRegion>Chuncheon 24252</wicri:noRegion></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 wicri:level="4"><nlm:affiliation>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName><placeName><settlement type="city">Tokyo</settlement><region type="province">Région de Kantō</region></placeName></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 wicri:level="1"><nlm:affiliation>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia.</nlm:affiliation><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea>Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982</wicri:regionArea><wicri:noRegion>Al-Ahsa 31982</wicri:noRegion></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><affiliations><list><country><li>Arabie saoudite</li><li>Corée du Sud</li><li>Japon</li></country><region><li>Préfecture de Gifu</li><li>Région de Kantō</li><li>Région du Chūbu</li></region><settlement><li>Gifu (ville)</li><li>Tokyo</li></settlement><orgName><li>Université de Gifu</li><li>Université de Tokyo</li></orgName></list><tree><country name="Arabie saoudite"><noRegion><name sortKey="Kandeel, Mahmoud" sort="Kandeel, Mahmoud" uniqKey="Kandeel M" first="Mahmoud" last="Kandeel">Mahmoud Kandeel</name></noRegion><name sortKey="Al Nazawi, Mohammed" sort="Al Nazawi, Mohammed" uniqKey="Al Nazawi M" first="Mohammed" last="Al-Nazawi">Mohammed Al-Nazawi</name><name sortKey="Al Taher, Abdulla" sort="Al Taher, Abdulla" uniqKey="Al Taher A" first="Abdulla" last="Al-Taher">Abdulla Al-Taher</name></country><country name="Japon"><region name="Région de Kantō"><name sortKey="Yamamoto, Mizuki" sort="Yamamoto, Mizuki" uniqKey="Yamamoto M" first="Mizuki" last="Yamamoto">Mizuki Yamamoto</name></region><name sortKey="Inoue, Jun Ichiro" sort="Inoue, Jun Ichiro" uniqKey="Inoue J" first="Jun-Ichiro" last="Inoue">Jun-Ichiro Inoue</name><name sortKey="Oh Hashi, Kentaro" sort="Oh Hashi, Kentaro" uniqKey="Oh Hashi K" first="Kentaro" last="Oh-Hashi">Kentaro Oh-Hashi</name><name sortKey="Watanabe, Aya" sort="Watanabe, Aya" uniqKey="Watanabe A" first="Aya" last="Watanabe">Aya Watanabe</name></country><country name="Corée du Sud"><noRegion><name sortKey="Park, Byoung Kwon" sort="Park, Byoung Kwon" uniqKey="Park B" first="Byoung Kwon" last="Park">Byoung Kwon Park</name></noRegion><name sortKey="Kwon, Hyung Joo" sort="Kwon, Hyung Joo" uniqKey="Kwon H" first="Hyung-Joo" last="Kwon">Hyung-Joo Kwon</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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