Structural insight into the cGAS active site explains differences between therapeutically relevant species
Abstract Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerou...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01481-7 |
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| author | Alexander M. Skeldon Li Wang Nicolas Sgarioto Ramsay E. Beveridge Silas Chan Stephane Dorich Valerie Dumais Nadine Fradet Samuel Gaudreault Philippe LeGros Daniel McKay Ria Seliniotakis Daniel V. Sietsema Lingling Zhang Marc-Olivier Boily Jason D. Burch Alex Caron Lee D. Fader Lodoe Lama Wei Xie Dinshaw J. Patel Thomas Tuschl Michael A. Crackower Kelly A. Pike |
| author_facet | Alexander M. Skeldon Li Wang Nicolas Sgarioto Ramsay E. Beveridge Silas Chan Stephane Dorich Valerie Dumais Nadine Fradet Samuel Gaudreault Philippe LeGros Daniel McKay Ria Seliniotakis Daniel V. Sietsema Lingling Zhang Marc-Olivier Boily Jason D. Burch Alex Caron Lee D. Fader Lodoe Lama Wei Xie Dinshaw J. Patel Thomas Tuschl Michael A. Crackower Kelly A. Pike |
| author_sort | Alexander M. Skeldon |
| collection | DOAJ |
| description | Abstract Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies. |
| format | Article |
| id | doaj-art-b503103e367541b0b22097529d58ce01 |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-b503103e367541b0b22097529d58ce012025-08-20T03:41:46ZengNature PortfolioCommunications Chemistry2399-36692025-03-018111510.1038/s42004-025-01481-7Structural insight into the cGAS active site explains differences between therapeutically relevant speciesAlexander M. Skeldon0Li Wang1Nicolas Sgarioto2Ramsay E. Beveridge3Silas Chan4Stephane Dorich5Valerie Dumais6Nadine Fradet7Samuel Gaudreault8Philippe LeGros9Daniel McKay10Ria Seliniotakis11Daniel V. Sietsema12Lingling Zhang13Marc-Olivier Boily14Jason D. Burch15Alex Caron16Lee D. Fader17Lodoe Lama18Wei Xie19Dinshaw J. Patel20Thomas Tuschl21Michael A. Crackower22Kelly A. Pike23Ventus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsVentus TherapeuticsLaboratory for RNA Molecular Biology, The Rockefeller UniversityStructural Biology Program, Memorial Sloan-Kettering Cancer CenterStructural Biology Program, Memorial Sloan-Kettering Cancer CenterLaboratory for RNA Molecular Biology, The Rockefeller UniversityVentus TherapeuticsVentus TherapeuticsAbstract Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies.https://doi.org/10.1038/s42004-025-01481-7 |
| spellingShingle | Alexander M. Skeldon Li Wang Nicolas Sgarioto Ramsay E. Beveridge Silas Chan Stephane Dorich Valerie Dumais Nadine Fradet Samuel Gaudreault Philippe LeGros Daniel McKay Ria Seliniotakis Daniel V. Sietsema Lingling Zhang Marc-Olivier Boily Jason D. Burch Alex Caron Lee D. Fader Lodoe Lama Wei Xie Dinshaw J. Patel Thomas Tuschl Michael A. Crackower Kelly A. Pike Structural insight into the cGAS active site explains differences between therapeutically relevant species Communications Chemistry |
| title | Structural insight into the cGAS active site explains differences between therapeutically relevant species |
| title_full | Structural insight into the cGAS active site explains differences between therapeutically relevant species |
| title_fullStr | Structural insight into the cGAS active site explains differences between therapeutically relevant species |
| title_full_unstemmed | Structural insight into the cGAS active site explains differences between therapeutically relevant species |
| title_short | Structural insight into the cGAS active site explains differences between therapeutically relevant species |
| title_sort | structural insight into the cgas active site explains differences between therapeutically relevant species |
| url | https://doi.org/10.1038/s42004-025-01481-7 |
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