Design, synthesis, and biological evaluation of covalent inhibitors targeting influenza virus hemagglutinin

doi:10.5246/jcps.2024.01.001

Abstract

Abstract:

The ongoing evolution of influenza strains and the limited effectiveness of existing anti-influenza drugs underscore the imperative for novel therapeutics. In addressing this, we developed and synthesized several sialic acid (SA) analogs, designed as potential covalent inhibitors by targeting lysine residues (Lys133 and Lys222) proximal to the substrate binding site of hemagglutinin (HA). The affinities of these compounds for HA were meticulously assessed using surface plasmon resonance (SPR). Intriguingly, all target compounds exhibited superior affinities for HA compared to the parent compound SA. Notably, compound 1d demonstrated a binding potency similar to that of the positive control (2,6-SLN), with K_D values of 38.2 μM and 39.6 μM, respectively. Importantly, all compounds demonstrated non-cytotoxicity to MDCK cells, and compound 1d displayed robust inhibitory effects on the influenza virus in vitro. The development of covalent inhibitors targeting HA, as outlined in this study, presented a rational and promising strategy for the creation of potent HA inhibitors.

Key words: Sialic acid, Influenza virus, Hemagglutinin, Inhibitors, Covalent binding

Supporting:

Nian Wang, Chenning Li, Chenxi Cheng, Jianzhong Chen, Pengfei Wang, Xun Lv, Xuebing Li. Design, synthesis, and biological evaluation of covalent inhibitors targeting influenza virus hemagglutinin[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(1): 1-14.

Figures/Tables 6

References 30

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