Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19
Abstract Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits rema...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/fb9698cf840e4e28863c13aafd4f244e |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:fb9698cf840e4e28863c13aafd4f244e |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:fb9698cf840e4e28863c13aafd4f244e2021-12-02T17:12:25ZBispecific repurposed medicines targeting the viral and immunological arms of COVID-1910.1038/s41598-021-92416-42045-2322https://doaj.org/article/fb9698cf840e4e28863c13aafd4f244e2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92416-4https://doaj.org/toc/2045-2322Abstract Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.Martin A. RedheadC. David OwenLennart BrewitzAmelia H. CollettePetra LukacikClaire Strain-DamerellSean W. RobinsonPatrick M. CollinsPhilipp SchäferMark SwindellsChris J. RadouxIva Navratilova HopkinsDaren FearonAlice DouangamathFrank von DelftTika R. MallaLaura VangeelThomas VercruysseJan ThibautPieter LeyssenTu-Trinh NguyenMitchell HullAnthony TumberDavid J. HallettChristopher J. SchofieldDavid I. StuartAndrew L. HopkinsMartin A. WalshNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Martin A. Redhead C. David Owen Lennart Brewitz Amelia H. Collette Petra Lukacik Claire Strain-Damerell Sean W. Robinson Patrick M. Collins Philipp Schäfer Mark Swindells Chris J. Radoux Iva Navratilova Hopkins Daren Fearon Alice Douangamath Frank von Delft Tika R. Malla Laura Vangeel Thomas Vercruysse Jan Thibaut Pieter Leyssen Tu-Trinh Nguyen Mitchell Hull Anthony Tumber David J. Hallett Christopher J. Schofield David I. Stuart Andrew L. Hopkins Martin A. Walsh Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| description |
Abstract Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation. |
| format |
article |
| author |
Martin A. Redhead C. David Owen Lennart Brewitz Amelia H. Collette Petra Lukacik Claire Strain-Damerell Sean W. Robinson Patrick M. Collins Philipp Schäfer Mark Swindells Chris J. Radoux Iva Navratilova Hopkins Daren Fearon Alice Douangamath Frank von Delft Tika R. Malla Laura Vangeel Thomas Vercruysse Jan Thibaut Pieter Leyssen Tu-Trinh Nguyen Mitchell Hull Anthony Tumber David J. Hallett Christopher J. Schofield David I. Stuart Andrew L. Hopkins Martin A. Walsh |
| author_facet |
Martin A. Redhead C. David Owen Lennart Brewitz Amelia H. Collette Petra Lukacik Claire Strain-Damerell Sean W. Robinson Patrick M. Collins Philipp Schäfer Mark Swindells Chris J. Radoux Iva Navratilova Hopkins Daren Fearon Alice Douangamath Frank von Delft Tika R. Malla Laura Vangeel Thomas Vercruysse Jan Thibaut Pieter Leyssen Tu-Trinh Nguyen Mitchell Hull Anthony Tumber David J. Hallett Christopher J. Schofield David I. Stuart Andrew L. Hopkins Martin A. Walsh |
| author_sort |
Martin A. Redhead |
| title |
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| title_short |
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| title_full |
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| title_fullStr |
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| title_full_unstemmed |
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19 |
| title_sort |
bispecific repurposed medicines targeting the viral and immunological arms of covid-19 |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/fb9698cf840e4e28863c13aafd4f244e |
| work_keys_str_mv |
AT martinaredhead bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT cdavidowen bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT lennartbrewitz bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT ameliahcollette bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT petralukacik bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT clairestraindamerell bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT seanwrobinson bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT patrickmcollins bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT philippschafer bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT markswindells bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT chrisjradoux bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT ivanavratilovahopkins bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT darenfearon bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT alicedouangamath bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT frankvondelft bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT tikarmalla bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT lauravangeel bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT thomasvercruysse bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT janthibaut bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT pieterleyssen bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT tutrinhnguyen bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT mitchellhull bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT anthonytumber bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT davidjhallett bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT christopherjschofield bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT davidistuart bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT andrewlhopkins bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 AT martinawalsh bispecificrepurposedmedicinestargetingtheviralandimmunologicalarmsofcovid19 |
| _version_ |
1718381416594538496 |