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

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.