作者: Tan, Eric ; Jonckers, Tim H. M. ; Alcázar, Jesus ; Stoops, Bart ; Yin, Yanting ; Carbajo, Rodrigo J. ; Lutter, Ferdinand H. ; Rigaux, Peter ; Martinez, Carol ; Cooymans, Ludwig ; Roymans, Dirk ; Tran, Minh T. ; Jacoby, Edgar ; Hu, Lili ; van Vlijmen, Herman ; Grosse, Sandrine ; Yu, Xiaodi ; Pieters, Serge ; Sharma, Sujata

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 in vitro antiviral activity and pronounced in vivo 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.

Communications Biology

Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor

Article

作者: Miller, Robyn ; Bhaumik, Anusarka ; Patrick, Aaron ; Jonckers, Tim H M ; Decroly, Etienne ; Roymans, Dirk ; Rigaux, Peter ; Anson, Brandon ; Sutto-Ortiz, Priscila ; Verheyen, Nick ; Shareef, Afzaal ; Van Vlijmen, Herman ; Abeywickrema, Pravien ; Piassek, Madison ; Behera, Ishani ; Adhikary, Suraj ; Yu, Xiaodi ; Fung, Amy ; Ysebaert, Nina ; Herschke, Florence ; McLellan, Jason S ; Grosse, Sandrine ; Jacoby, Edgar ; De Bruyn, Suzanne ; Sharma, Sujata ; Carbajo, Rodrigo J ; Bonneux, Brecht ; Pham, Quyen ; Fearns, Rachel ; Jin, Zhinan

AbstractThe respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.

100 项与 JNJ-8003 相关的药物交易

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