Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors

The crystal structure of sialidase from C. perfringens, a pathogenic bacterium causing various gastrointestinal diseases, was determined in complex with a potent natural polyphenolic geranylated flavonoid-based inhibitor. The complex structure and comparative kinetic studies revealed that the geranyl group and C3′ hydroxyl group of the flavonoid backbone contribute to inhibition of the bacterial sialidase and generation of the stable enzyme–inhibitor complex.
Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme–inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents.