Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease

Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry
Dominga RogolinoMauro Carcelli

Abstract

The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg²⁺ or Mn²⁺) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1-6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure-activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg²⁺, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarb...Continue Reading

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Citations

Mar 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Valeria FrancesconiMichele Tonelli
Nov 15, 2016·Metallomics : Integrated Biometal Science·Franco BisceglieGiorgio Pelosi
Nov 28, 2017·Journal of Inorganic Biochemistry·Franco BisceglieGiorgio Pelosi
Aug 17, 2021·Frontiers in Pharmacology·Monika KowalczykWłodzimierz Lewandowski
Aug 24, 2021·Acta Crystallographica. Section E, Crystallographic Communications·Ming Yueh TanEdward R T Tiekink
Nov 30, 2021·Journal of Biomolecular Structure & Dynamics·Sunil Kumar, Mukesh Choudhary
Aug 20, 2020·Mini Reviews in Medicinal Chemistry·Alok Kumar MoharanaBharat Bhusan Subudhi

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