9ED2
CryoEM map of Respiratory Syncytial Virus Polymerase with Non-Nucleoside Inhibitor compound 21
This is a non-PDB format compatible entry.
Summary for 9ED2
| Entry DOI | 10.2210/pdb9ed2/pdb |
| EMDB information | 47931 |
| Descriptor | RNA-directed RNA polymerase L, Phosphoprotein, Compound 21, ... (4 entities in total) |
| Functional Keywords | non-nucleoside inhibitor, complex, polymerase, rsv, viral protein, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | human respiratory syncytial virus More |
| Total number of polymer chains | 6 |
| Total formula weight | 371114.16 |
| Authors | Yin, Y.,Tran, M.T.,Yu, X.,Jonckers, T.,Carney, S. (deposition date: 2024-11-15, release date: 2025-09-24) |
| Primary citation | Carney, S.M.,Grosse, S.,Yin, Y.,Tran, M.T.,Kalin, J.H.,Jacoby, E.,Fung, A.,Simmons, N.,Xie, X.,Bhaumik, A.,Carbajo, R.J.,Piassek, M.,Miller, R.,Hu, L.,Lemmens, C.,Lutter, F.H.,Pieters, S.,Rombouts, G.,Vetrano, I.,Oehlrich, D.,Tomaso, S.,Lozada, K.,Garcia, M.O.,Anson, B.,De Bruyn, S.,Smith-Monroy, C.,Neefs, J.M.,Conceicao-Neto, N.,Kesteleyn, B.,Fino, R.,Stoops, B.,van Vlijmen, H.,Patrick, A.N.,Yu, X.,Wong, V.,Krosky, D.J.,Abeywickrema, P.,Ortiz-Meoz, R.F.,Mason, S.W.,Jin, Z.,Sharma, S.,Jonckers, T.H.M. DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors. J.Med.Chem., 68:6407-6430, 2025 Cited by PubMed Abstract: Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and characterized its binding to a novel pocket within the capping domain of the polymerase. Here, we describe our strategy to diversify the chemical matter targeting this site by screening our DNA-encoded chemical libraries, leading to the discovery of a novel and potent series of molecules that inhibits RSV polymerase's biochemical activity, as well as its viral replication in cells. Structural analysis via cryo-EM revealed novel contacts made within the capping domain binding pocket. By leveraging these structural insights for preliminary SAR exploration, we generated analogues for which potency and metabolic stability were improved more than 60- and 40-fold, respectively, over the initial hit. This work provides a path forward for further advanced SAR exploration and development of therapeutics against RSV. PubMed: 40042938DOI: 10.1021/acs.jmedchem.4c02906 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.72 Å) |
Structure validation
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