Xiayang Qiu

Xiayang Qiu

Xiayang Qiu

Ye Che

Ye Che

Ye Che

+ 0 Evaluators

Targeted covalent enzyme inhibitors have been experiencing resurgence as a medicinal chemistry design strategy in recent years, owing to their unique pharmacological advantages {1,2}: covalent inhibitors often exhibit slow target offset, increased binding potency and biochemical efficiency, as well as enhanced selectivity, prolonged pharmacodynamic effects and reduced propensity for target-based drug resistance. Neuraminidase, on the envelope of the influenza virus, represents an important drug target for the prevention of the spread of influenza infection. Oseltamivir and zanamivir, two approved antiviral drugs, work by blocking the function of neuraminidase via non-covalent inhibition, thus preventing the virus from reproducing by budding from the host cell. Stephen G Withers and coworkers had previously shown that neuraminidase catalyzes sialic acid cleavage by a mechanism involving a covalent intermediate {3}. Here, they have designed 2,3-difluoro sialic acid analogs that bind covalently to the viral neuraminidase active site, but release very slowly, thus disabling the enzyme, and that at the same time do not inhibit human neuraminidase, or only inhibit it at much lower affinity than oseltamivir and zanamivir. The mode of action of covalent inhibition has been confirmed by structural and biophysical studies. Full text of this article

Roland Seifert

Roland Seifert

Roland Seifert

+ -1 Evaluators

Influenza infections constitute a huge medical problem. The currently available drugs against influenza are not very effective, and resistance constitutes a major problem, too. The viral neuraminidase plays an important role in virus infection of host cells. Here, a new class of covalent neuraminidase inhibitors is developed. The new compounds show also efficacy in cells and animal models. Moreover, they show effects against influenza viruses that are resistant against conventional neuraminidase inhibitors. This paper is an excellent example how the combination of crystallography, medicinal chemistry and cell biology can lead to the development of promising new drugs. The crucial question is whether resistance against the new inhibitors will emerge. Based on past experience with antimicrobials in general, such development is not unlikely to occur.