A rigid bicyclic platform for the generation of conformationally locked neuraminidase inhibitors

Abstract

Rapid mutation of the influenza virus through genetic mixing raises the prospect of new strains that are both highly transmissible and highly lethal, and which have the ability to evade both immunization strategies (through mutation of hemagglutinin) and current therapies (through mutation of neuraminidase). Inspired by a need for next-generation therapeutics, a synthetic strategy for a new class of rigid, bicyclic inhibitors of influenza neuraminidase is reported.

Figure 1

Neuraminidase function and inhibition. (A) Enzymatic function; (B) important interactions for inhibition; (C) structures of the three clinically used inhibitors and comparison with truncated analogs.

Scheme 1. An Efficient Bicyclic Sulfone Synthesis

Figure 2

X-ray structural data and in silico docking results. (A) Structure of peramivir bound in the enzyme active site (from PDB 2HTU); (B) structure of 5a (CCDC 766248); (C) overlay of enzyme-bound peramivir (green) with the docked structure of 15 (yellow; calculated in MOLOC); (D) peramivir and 15 pictured inside the neuraminidase active site; (E) small-molecule X-ray structure of the ethyl ester hydrochloride of 10.

Scheme 2. Regiochemical Switch Employed in the Synthesis of Bicyclic Neuraminidase Inhibitors

Figure 3

Lineweaver–Burk plots confirming competitive neuraminidase inhibition for all three tested compouds in NP40-inactivated influenza A/Brisbane/59/2007(H1N1) virus.