Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex.
Jiménez-Somarribas A, Mao S, Yoon JJ, Weisshaar M, Cox RM, Marengo JR, Mitchell DG, Morehouse ZP, Yan D, Solis I, Liotta DC, Natchus MG, Plemper RK.
Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into a recombinant RSV virus and applied the strain to high-throughput screening. Counterscreening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50 = 0.21 μM, selectivity index (SI) 40) and scaffold. Resynthesis confirmed the potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogues (i.e., 8n: EC50 = 0.06 μM, SI 500) that establish a platform for the development of a therapeutic candidate.