9c7y
Structure Of Respiratory Syncytial Virus Polymerase in complex with JNJ-2729
Structural highlights
FunctionL_HRSVA Displays RNA-directed RNA polymerase, mRNA guanylyl transferase, mRNA (guanine-N(7)-)-methyltransferase and poly(A) synthetase activities. The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). Functions either as transcriptase or as replicase. The transcriptase synthesizes subsequently the subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The replicase mode is dependent on intracellular protein N concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals (By similarity).[1] Publication Abstract from PubMedDespite 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. Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.,Tran MT, Grosse S, Carbajo RJ, Jacoby E, Yin Y, Yu X, Martinez C, Stoops B, Cooymans L, Hu L, Lutter FH, Pieters S, Tan E, Alcazar J, Roymans D, van Vlijmen H, Rigaux P, Sharma S, Jonckers THM ACS Med Chem Lett. 2024 Aug 2;15(9):1549-1558. doi: , 10.1021/acsmedchemlett.4c00272. eCollection 2024 Sep 12. PMID:39291020[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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