9C7Y
Structure Of Respiratory Syncytial Virus Polymerase in complex with JNJ-2729
This is a non-PDB format compatible entry.
Summary for 9C7Y
| Entry DOI | 10.2210/pdb9c7y/pdb |
| EMDB information | 45296 |
| Descriptor | RNA-directed RNA polymerase L, Phosphoprotein, (2S)-1,1,1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-[(4M)-4-(8-methoxyquinolin-6-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol (3 entities in total) |
| Functional Keywords | non-nucleoside inhibitor, complex, polymerase, rsv, viral protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Human respiratory syncytial virus A2 More |
| Total number of polymer chains | 5 |
| Total formula weight | 371319.86 |
| Authors | |
| Primary citation | Tran, M.T.,Grosse, S.,Carbajo, R.J.,Jacoby, E.,Yin, Y.,Yu, X.,Martinez, C.,Stoops, B.,Cooymans, L.,Hu, L.,Lutter, F.H.,Pieters, S.,Tan, E.,Alcazar, J.,Roymans, D.,van Vlijmen, H.,Rigaux, P.,Sharma, S.,Jonckers, T.H.M. Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors. Acs Med.Chem.Lett., 15:1549-1558, 2024 Cited by PubMed Abstract: Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent antiviral activity and pronounced efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters. PubMed: 39291020DOI: 10.1021/acsmedchemlett.4c00272 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.24 Å) |
Structure validation
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