Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase.
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| Autori principali: | , , , , , , , , , , , |
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| Natura: | Artículo científico |
| Lingua: | en |
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Bioorganic & medicinal chemistry letters
2025
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| author | Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L |
| author_facet | Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L |
| collection | PubMed - marine biology |
| contents | Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase. Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L Humans Binding Sites Crystallography, X-Ray Dose-Response Relationship, Drug Enzyme Inhibitors Models, Molecular Molecular Structure Nucleotidyltransferases Structure-Activity Relationship Guanosine Monophosphate Adenosine Monophosphate Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC = 370 nM). An X-ray co-crystal structure at 2.75 Å resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site. |
| format | Artículo científico |
| id | pubmed_39521150 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Bioorganic & medicinal chemistry letters |
| record_format | pubmed |
| spellingShingle | Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase. Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L Humans Binding Sites Crystallography, X-Ray Dose-Response Relationship, Drug Enzyme Inhibitors Models, Molecular Molecular Structure Nucleotidyltransferases Structure-Activity Relationship Guanosine Monophosphate Adenosine Monophosphate Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase. Kissai, Mildred Chin, Emily N Martínez-Peña, Francisco Sulpizio, Ariana Stout, E Paige Usui, Ippei Barmare, Farhana Sanchez, Brittany Esquenazi, Eduardo Stanfield, Robyn L Wilson, Ian A Lairson, Luke L Humans Binding Sites Crystallography, X-Ray Dose-Response Relationship, Drug Enzyme Inhibitors Models, Molecular Molecular Structure Nucleotidyltransferases Structure-Activity Relationship Guanosine Monophosphate Adenosine Monophosphate Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC = 370 nM). An X-ray co-crystal structure at 2.75 Å resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site. |
| title | Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase. |
| topic | Humans Binding Sites Crystallography, X-Ray Dose-Response Relationship, Drug Enzyme Inhibitors Models, Molecular Molecular Structure Nucleotidyltransferases Structure-Activity Relationship Guanosine Monophosphate Adenosine Monophosphate Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase |
| url | https://pubmed.ncbi.nlm.nih.gov/39521150/ |