Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins
A novel series of macrocyclic pyrazolo[1,5- ]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, su...
Gespeichert in:
| Veröffentlicht in: | ACS medicinal chemistry letters 2020-06, Vol.11 (6), p.1145-1151 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1151 |
|---|---|
| container_issue | 6 |
| container_start_page | 1145 |
| container_title | ACS medicinal chemistry letters |
| container_volume | 11 |
| creator | Yamaguchi-Sasaki, Toru Tokura, Seiken Ogata, Yuya Kawaguchi, Takanori Sugaya, Yutaka Takahashi, Ryo Iwakiri, Kanako Abe-Kumasaka, Tomoko Yoshida, Ippei Arikawa, Kaho Sugiyama, Hiroyuki Kanuma, Kosuke |
| description | A novel series of macrocyclic pyrazolo[1,5-
]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as
,
, and
, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition,
showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that
binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of
. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins. |
| doi_str_mv | 10.1021/acsmedchemlett.0c00008 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7294717</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2415290372</sourcerecordid><originalsourceid>FETCH-LOGICAL-c414t-b18b87faca76abd191e82c3ac070d9d20f6198786a1b041e6f0a5a5538c367e73</originalsourceid><addsrcrecordid>eNpVUdtKAzEQDaJorf5CyaMvW5O9JXkRxHoDRfH6GGazWRvZbmqSFfbvTWkVOy8zMOecuRyEJpRMKUnpKSi_0LWa60WrQ5gSRWLwHTSiIudJwVmx-68-QIfefxJSCsbIPjrI0qIgQuQjNJ8Zr-y3dgO2DQb8aIPuAp710OLbbm4qE6xbtd5NWycvw1Jj6Gp83weIsCftl8ZBhAz4eejUEEzkvRnXe3zVe2M7_Oiioun8EdproPX6eJPH6PXq8uXiJrl7uL69OL9LVE7zkFSUV5w1oICVUNVUUM1TlYEijNSiTklTUsEZL4FWJKe6bAgUUBQZV1nJNMvG6Gytu-yr1YfiNQ5auXRmAW6QFozc7nRmLj_st2SpyBldCZxsBJz96rUPchFfpNsWOm17L9OcFqkgGUsjtFxDlbPeO938jaFErmyS2zbJjU2ROPm_5B_t15fsBxQulas</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2415290372</pqid></control><display><type>article</type><title>Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>ACS Publications</source><source>PubMed Central</source><creator>Yamaguchi-Sasaki, Toru ; Tokura, Seiken ; Ogata, Yuya ; Kawaguchi, Takanori ; Sugaya, Yutaka ; Takahashi, Ryo ; Iwakiri, Kanako ; Abe-Kumasaka, Tomoko ; Yoshida, Ippei ; Arikawa, Kaho ; Sugiyama, Hiroyuki ; Kanuma, Kosuke</creator><creatorcontrib>Yamaguchi-Sasaki, Toru ; Tokura, Seiken ; Ogata, Yuya ; Kawaguchi, Takanori ; Sugaya, Yutaka ; Takahashi, Ryo ; Iwakiri, Kanako ; Abe-Kumasaka, Tomoko ; Yoshida, Ippei ; Arikawa, Kaho ; Sugiyama, Hiroyuki ; Kanuma, Kosuke</creatorcontrib><description>A novel series of macrocyclic pyrazolo[1,5-
]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as
,
, and
, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition,
showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that
binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of
. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.0c00008</identifier><identifier>PMID: 32550994</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Letter</subject><ispartof>ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1145-1151</ispartof><rights>Copyright © 2020 American Chemical Society.</rights><rights>Copyright © 2020 American Chemical Society 2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-b18b87faca76abd191e82c3ac070d9d20f6198786a1b041e6f0a5a5538c367e73</citedby><cites>FETCH-LOGICAL-c414t-b18b87faca76abd191e82c3ac070d9d20f6198786a1b041e6f0a5a5538c367e73</cites><orcidid>0000-0003-2620-5250</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294717/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294717/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,2763,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32550994$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamaguchi-Sasaki, Toru</creatorcontrib><creatorcontrib>Tokura, Seiken</creatorcontrib><creatorcontrib>Ogata, Yuya</creatorcontrib><creatorcontrib>Kawaguchi, Takanori</creatorcontrib><creatorcontrib>Sugaya, Yutaka</creatorcontrib><creatorcontrib>Takahashi, Ryo</creatorcontrib><creatorcontrib>Iwakiri, Kanako</creatorcontrib><creatorcontrib>Abe-Kumasaka, Tomoko</creatorcontrib><creatorcontrib>Yoshida, Ippei</creatorcontrib><creatorcontrib>Arikawa, Kaho</creatorcontrib><creatorcontrib>Sugiyama, Hiroyuki</creatorcontrib><creatorcontrib>Kanuma, Kosuke</creatorcontrib><title>Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins</title><title>ACS medicinal chemistry letters</title><addtitle>ACS Med Chem Lett</addtitle><description>A novel series of macrocyclic pyrazolo[1,5-
]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as
,
, and
, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition,
showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that
binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of
. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.</description><subject>Letter</subject><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVUdtKAzEQDaJorf5CyaMvW5O9JXkRxHoDRfH6GGazWRvZbmqSFfbvTWkVOy8zMOecuRyEJpRMKUnpKSi_0LWa60WrQ5gSRWLwHTSiIudJwVmx-68-QIfefxJSCsbIPjrI0qIgQuQjNJ8Zr-y3dgO2DQb8aIPuAp710OLbbm4qE6xbtd5NWycvw1Jj6Gp83weIsCftl8ZBhAz4eejUEEzkvRnXe3zVe2M7_Oiioun8EdproPX6eJPH6PXq8uXiJrl7uL69OL9LVE7zkFSUV5w1oICVUNVUUM1TlYEijNSiTklTUsEZL4FWJKe6bAgUUBQZV1nJNMvG6Gytu-yr1YfiNQ5auXRmAW6QFozc7nRmLj_st2SpyBldCZxsBJz96rUPchFfpNsWOm17L9OcFqkgGUsjtFxDlbPeO938jaFErmyS2zbJjU2ROPm_5B_t15fsBxQulas</recordid><startdate>20200611</startdate><enddate>20200611</enddate><creator>Yamaguchi-Sasaki, Toru</creator><creator>Tokura, Seiken</creator><creator>Ogata, Yuya</creator><creator>Kawaguchi, Takanori</creator><creator>Sugaya, Yutaka</creator><creator>Takahashi, Ryo</creator><creator>Iwakiri, Kanako</creator><creator>Abe-Kumasaka, Tomoko</creator><creator>Yoshida, Ippei</creator><creator>Arikawa, Kaho</creator><creator>Sugiyama, Hiroyuki</creator><creator>Kanuma, Kosuke</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2620-5250</orcidid></search><sort><creationdate>20200611</creationdate><title>Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins</title><author>Yamaguchi-Sasaki, Toru ; Tokura, Seiken ; Ogata, Yuya ; Kawaguchi, Takanori ; Sugaya, Yutaka ; Takahashi, Ryo ; Iwakiri, Kanako ; Abe-Kumasaka, Tomoko ; Yoshida, Ippei ; Arikawa, Kaho ; Sugiyama, Hiroyuki ; Kanuma, Kosuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-b18b87faca76abd191e82c3ac070d9d20f6198786a1b041e6f0a5a5538c367e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Letter</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamaguchi-Sasaki, Toru</creatorcontrib><creatorcontrib>Tokura, Seiken</creatorcontrib><creatorcontrib>Ogata, Yuya</creatorcontrib><creatorcontrib>Kawaguchi, Takanori</creatorcontrib><creatorcontrib>Sugaya, Yutaka</creatorcontrib><creatorcontrib>Takahashi, Ryo</creatorcontrib><creatorcontrib>Iwakiri, Kanako</creatorcontrib><creatorcontrib>Abe-Kumasaka, Tomoko</creatorcontrib><creatorcontrib>Yoshida, Ippei</creatorcontrib><creatorcontrib>Arikawa, Kaho</creatorcontrib><creatorcontrib>Sugiyama, Hiroyuki</creatorcontrib><creatorcontrib>Kanuma, Kosuke</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamaguchi-Sasaki, Toru</au><au>Tokura, Seiken</au><au>Ogata, Yuya</au><au>Kawaguchi, Takanori</au><au>Sugaya, Yutaka</au><au>Takahashi, Ryo</au><au>Iwakiri, Kanako</au><au>Abe-Kumasaka, Tomoko</au><au>Yoshida, Ippei</au><au>Arikawa, Kaho</au><au>Sugiyama, Hiroyuki</au><au>Kanuma, Kosuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins</atitle><jtitle>ACS medicinal chemistry letters</jtitle><addtitle>ACS Med Chem Lett</addtitle><date>2020-06-11</date><risdate>2020</risdate><volume>11</volume><issue>6</issue><spage>1145</spage><epage>1151</epage><pages>1145-1151</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><abstract>A novel series of macrocyclic pyrazolo[1,5-
]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as
,
, and
, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition,
showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that
binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of
. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32550994</pmid><doi>10.1021/acsmedchemlett.0c00008</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-2620-5250</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1948-5875 |
| ispartof | ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1145-1151 |
| issn | 1948-5875 1948-5875 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7294717 |
| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ACS Publications; PubMed Central |
| subjects | Letter |
| title | Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T03%3A27%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20a%20Potent%20Dual%20Inhibitor%20of%20Wild-Type%20and%20Mutant%20Respiratory%20Syncytial%20Virus%20Fusion%20Proteins&rft.jtitle=ACS%20medicinal%20chemistry%20letters&rft.au=Yamaguchi-Sasaki,%20Toru&rft.date=2020-06-11&rft.volume=11&rft.issue=6&rft.spage=1145&rft.epage=1151&rft.pages=1145-1151&rft.issn=1948-5875&rft.eissn=1948-5875&rft_id=info:doi/10.1021/acsmedchemlett.0c00008&rft_dat=%3Cproquest_pubme%3E2415290372%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2415290372&rft_id=info:pmid/32550994&rfr_iscdi=true |