The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors

Abstract

Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure-activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC = 0.1 ± 0.04 μm, H3N2 IC = 0.26 ± 0.18 μm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.

Antivirals Targeting the Neuraminidase

“…Different oseltamivir derivatives targeting the 150-cavity (e.g., modifications at C-5 NH 2 position, addition of N/O/C fragment/linker, and lipophilic side chains at C-5) were synthesized. These derivatives had significantly improved potency (Wang et al 2010;Xie et al 2014;Lin et al 2018;Zhang et al 2018). As these inhibitors target the 150-cavity and can specifically inhibit only the group 1 NAs, including the A(H1N1)pdm09, they may provide a prospective way to design selective NA inhibitors.…”