Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS
SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in key steps of the viral life cycle, thus representing a top drug target. Functionality of N protein including liquid–liquid phase separation (LLPS) depends on its interaction with nucleic acids. Only the variants with N proteins functio...
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2021-01-01
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| Series: | QRB Discovery |
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| Online Access: | https://www.cambridge.org/core/product/identifier/S2633289221000120/type/journal_article |
| _version_ | 1811155757711753216 |
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| author | Mei Dang Jianxing Song |
| author_facet | Mei Dang Jianxing Song |
| author_sort | Mei Dang |
| collection | DOAJ |
| description | SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in key steps of the viral life cycle, thus representing a top drug target. Functionality of N protein including liquid–liquid phase separation (LLPS) depends on its interaction with nucleic acids. Only the variants with N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of N protein with Kd of 112.1 and 57.1 μM, respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to different variants. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex suggests a promising strategy for design of better anti-SARS-CoV-2 drugs from HCQ. |
| first_indexed | 2024-04-10T04:38:55Z |
| format | Article |
| id | doaj.art-b91799aca4874726b9edb703cc581487 |
| institution | Directory Open Access Journal |
| issn | 2633-2892 |
| language | English |
| last_indexed | 2024-04-10T04:38:55Z |
| publishDate | 2021-01-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | QRB Discovery |
| spelling | doaj.art-b91799aca4874726b9edb703cc5814872023-03-09T12:43:33ZengCambridge University PressQRB Discovery2633-28922021-01-01210.1017/qrd.2021.12Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPSMei Dang0https://orcid.org/0000-0002-2660-3323Jianxing Song1https://orcid.org/0000-0003-0224-6322Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, SingaporeDepartment of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, SingaporeSARS-CoV-2 nucleocapsid (N) protein plays the essential roles in key steps of the viral life cycle, thus representing a top drug target. Functionality of N protein including liquid–liquid phase separation (LLPS) depends on its interaction with nucleic acids. Only the variants with N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of N protein with Kd of 112.1 and 57.1 μM, respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to different variants. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex suggests a promising strategy for design of better anti-SARS-CoV-2 drugs from HCQ.https://www.cambridge.org/core/product/identifier/S2633289221000120/type/journal_articleHydroxychloroquineliquid–liquid phase separationNMR spectroscopynucleocapsid proteinSARS-CoV-2 |
| spellingShingle | Mei Dang Jianxing Song Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS QRB Discovery Hydroxychloroquine liquid–liquid phase separation NMR spectroscopy nucleocapsid protein SARS-CoV-2 |
| title | Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS |
| title_full | Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS |
| title_fullStr | Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS |
| title_full_unstemmed | Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS |
| title_short | Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS |
| title_sort | structural basis of anti sars cov 2 activity of hcq specific binding to n protein to disrupt its interaction with nucleic acids and llps |
| topic | Hydroxychloroquine liquid–liquid phase separation NMR spectroscopy nucleocapsid protein SARS-CoV-2 |
| url | https://www.cambridge.org/core/product/identifier/S2633289221000120/type/journal_article |
| work_keys_str_mv | AT meidang structuralbasisofantisarscov2activityofhcqspecificbindingtonproteintodisruptitsinteractionwithnucleicacidsandllps AT jianxingsong structuralbasisofantisarscov2activityofhcqspecificbindingtonproteintodisruptitsinteractionwithnucleicacidsandllps |