9ed2
CryoEM map of Respiratory Syncytial Virus Polymerase with Non-Nucleoside Inhibitor compound 21
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 PubMedRespiratory 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. DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors.,Carney SM, Grosse S, Yin Y, Tran MT, Kalin JH, Jacoby E, Fung A, Simmons N, Xie X, Bhaumik A, Carbajo RJ, Piassek M, Miller R, Hu L, Lemmens C, Lutter FH, Pieters S, Rombouts G, Vetrano I, Oehlrich D, Tomaso S, Lozada K, Garcia MO, Anson B, De Bruyn S, Smith-Monroy C, Neefs JM, Conceicao-Neto N, Kesteleyn B, Fino R, Stoops B, van Vlijmen H, Patrick AN, Yu X, Wong V, Krosky DJ, Abeywickrema P, Ortiz-Meoz RF, Mason SW, Jin Z, Sharma S, Jonckers THM J Med Chem. 2025 Mar 27;68(6):6407-6430. doi: 10.1021/acs.jmedchem.4c02906. Epub , 2025 Mar 5. PMID:40042938[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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