Inhibition of Influenza Entry by Organosilicon Compounds

Abstract

Hemagglutinin (HA) plays a critical role in the entry of influenza and thus HA is a target for the development of entry inhibitors as antivirals. One of the first small molecule inhibitors of influenza entry to be described was tert-butylhydroquinone (TBHQ), a commonly used antioxidant. This compound was shown to inhibit influenza containing Group 2 HA, such as H3 and H7 HA circulating in humans and avians. One limitation of TBHQ is the propensity to oxidize in solution, resulting in a less active form of the compound. Recently, our group has shown that the reactivity of TBHQ may be significantly reduced through substitution of one hydroxyl group with a methoxy, resulting in a concurrent increase in potency and a decrease in cytotoxicity. In this study, we demonstrate that the inhibitory capacity can be further improved by introducing tri-methyl silane (TMS) in place of the tert-butyl (TB) group. Silicon-based derivatives of TBHQ exhibited increased stability in solution compared to the parent TBHQ compound. Analysis using NMR spectroscopy revealed similar interaction patterns for the original and engineered compounds, although the TMS group was creating stronger hydrophobic contacts within the binding pocket on HA. Strikingly, TMS-containing compounds exhibited increased in vitro activity against pseudotyped and live influenza viruses carrying Group 2 HAs. In summary, we applied a novel strategy for chemical optimization of antiviral compounds and demonstrated that this approach can improve their stability and their potency for the target protein.