Structure-Based Discovery of Allosteric Inhibitors Targeting a New Druggable Site in the Respiratory Syncytial Virus Polymerase.

ABSTRACT: Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infections for which effective treatment options remain limited. Herein, we employed a computational structure-based design strategy aimed at identifying potential targets for a new class of allosteric inhibitors. Our investigation led to the discovery of a previously undisclosed allosteric binding site within the RSV polymerase, the large (L) protein. This discovery was achieved through a combination of virtual screening and molecular dynamics simulations. Subsequently, we identified two inhibitors, 6a and 10b, which both exhibited promising antiviral activity in the low micromolar range. Resistance profiling revealed a distinctive pattern in how RSV evaded treatment with this class of inhibitors.

SUBMITTER: Oraby AK 

PROVIDER: S-EPMC11112712 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature