Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease.
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 thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors.
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy.
Dominga
D
Rogolino
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy.
Alessia
A
Bacchi
Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Polo Universitario SS. Annunziata, 98158, Messina, Italy.
Laura
L
De Luca
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy.
Gabriele
G
Rispoli
Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, 07100, Sassari, Italy.
Mario
M
Sechi
Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium.
Annelies
A
Stevaert
Rega Institute for Medical Research, KU Leuven, 3000, Louvain, Belgium.
Lieve
L
Naesens
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124, Parma, Italy. mauro.carcelli@unipr.it.
Mauro
M
Carcelli
D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001681:Biological Assay; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009975:Orthomyxoviridae / Q000187:drug effects*; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*
D000447:Aldehydes; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D013882:Thiosemicarbazones; C062542:salicylaldehyde thiosemicarbazone; D004720:Endonucleases
Antiviral; Endonuclease; Influenza virus; Metal chelation; Thiosemicarbazone