Figure 7.

Models of incorporatedGS-646939translocated to the “i + 1” position inHRV,SARS-CoV-2,RSV, and, PIV-5. Structures are not optimized but serve as a guide to clashes that impair further incorporation, GS-646939 is shown in magenta. Following incorporation, translocation of the RNA to position the inhibitor in the first primer position is hindered by residues of motif C which coordinate the catalytic metals. For HRV (A), Cα of Gly-326 and NH of Asp-327 present a translocation obstacle to the 4ʹ-cyano of the incorporated inhibitor. A similar impediment to translocation exists for SARS-CoV-2 (B). Assuming translocation occurs, C=O of Tyr-325 presents a significant steric clash which would perturb proper primer positioning. This clash appears to be more significant in RSV (C) and PIV5 (D). HRV, human rhinovirus; PIV-5, parainfluenza virus 5; RdRp, RNA-dependent RNA polymerase; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.