2. Academic Validation
  3. DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors

DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors

  • J Med Chem. 2025 Mar 27;68(6):6407-6430. doi: 10.1021/acs.jmedchem.4c02906.
Sean M Carney 1,  Sandrine Grosse 2,  Yanting Yin 1,  Minh T Tran 2,  Jay H Kalin 1,  Edgar Jacoby 2,  Amy Fung 3,  Nicholas Simmons 4,  Xiaoming Xie 4,  Anusarka Bhaumik 1,  Rodrigo J Carbajo 5,  Madison Piassek 1,  Robyn Miller 1,  Lili Hu 2,  Cynthia Lemmens 2,  Ferdinand H Lutter 2,  Serge Pieters 2,  Geert Rombouts 2,  Irene Vetrano 2,  Daniel Oehlrich 2,  Sonia Tomaso 3,  Kate Lozada 3,  Miguel Osorio Garcia 3,  Brandon Anson 3,  Suzanne De Bruyn 2,  Constance Smith-Monroy 1,  Jean-Marc Neefs 2,  Nádia Conceição-Neto 2,  Bart Kesteleyn 2,  Roberto Fino 2,  Bart Stoops 2,  Herman van Vlijmen 2,  Aaron N Patrick 1,  Xiaodi Yu 1,  Victoria Wong 1,  Daniel J Krosky 1,  Pravien Abeywickrema 1,  Rodrigo F Ortiz-Meoz 1,  Stephen W Mason 3,  Zhinan Jin 3,  Sujata Sharma 1,  Tim H M Jonckers 2
Affiliations

Affiliations

  • 1 Janssen Research & Development, LLC, Johnson & Johnson Company, Spring House, Pennsylvania 19002, United States.
  • 2 Janssen Pharmaceutica N.V., Beerse 2340, Belgium.
  • 3 Janssen Research & Development, LLC, Johnson & Johnson Company, Brisbane, California 94005, United States.
  • 4 Janssen Research & Development, LLC, Johnson & Johnson Company, San Diego, California 92121, United States.
  • 5 Janssen-Cilag, S.A. Río Jarama, 75A, Toledo 45007, Spain.
PMID: 40042938 DOI: 10.1021/acs.jmedchem.4c02906
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.

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