Abstract
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.
Highlights
Viral and bacterial sialidases have been focused on as drug targets for the treatment of human infections (Soong et al, 2006; Memoli et al, 2008)
In order to demonstrate that flavonoid-based natural compounds extracted from P. tomentosa act as inhibitors of Cp-NanI, a comparative activity screen was performed
We found that diplacone is the most effective inhibitor among these flavonoids
Summary
Viral and bacterial sialidases have been focused on as drug targets for the treatment of human infections (Soong et al, 2006; Memoli et al, 2008). Drug discovery of inhibitors targeting sialidase has focused on either synthetic compounds through random screening or substrate (N-acetylneuraminic acid) mimics. These studies have mainly been targeted against sialidase from the influenza virus. There are several inhibitors that mimic the substrate, including zanamivir (Relenza), oseltamivir (Tamiflu; a cyclohexene derivative), peramivir (a cyclopentane-based inhibitor) and A-315675 (a pyrrolidine-based inhibitor; Kim et al, 2013). All of these compounds are based on 2-deoxy-2,3-dehydro-Nacetylneuraminic acid (Neu5Ac2en), a putative transitionstate analogue. The existence of drug-resistant strains against zanamivir (Gubareva et al, 1998), oseltamivir (Gubareva et al, 2001) and other antivirals (Tambic Andrasevic, 2004) have spurred on the need to discover innovative antiviral agents
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