Virtual Screening and Biological Validation of Novel Influenza Virus PA Endonuclease Inhibitors.
The influenza virus RNA-dependent RNA polymerase complex (RdRp), a heterotrimeric protein complex responsible for viral RNA transcription and replication, represents a primary target for antiviral drug development. One particularly attractive approach is interference with the endonucleolytic "cap-snatching" reaction by the RdRp subunit PA, more precisely by inhibiting its metal-dependent catalytic activity which resides in the N-terminal part of PA (PA-Nter). Almost all PA inhibitors (PAIs) thus far discovered bear pharmacophoric fragments with chelating motifs able to bind the bivalent metal ions in the catalytic core of PA-Nter. More recently, the availability of crystallographic structures of PA-Nter has enabled rational design of original PAIs with improved binding properties and antiviral potency. We here present a coupled pharmacophore/docking virtual screening approach that allowed us to identify PAIs with interesting inhibitory activity in a PA-Nter enzymatic assay. Moreover, antiviral activity in the low micromolar range was observed in cell-based influenza virus assays.
Dipartimento di Chimica e Farmacia, Università di Sassari , Via Vienna 2, 07100 Sassari, Italy.
Nicolino
N
Pala
Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Annelies
A
Stevaert
Istituto di Chimica Biomolecolare, CNR-Consiglio Nazionale delle Ricerche , Sassari, 07100 Li Punti Italy.
Roberto
R
Dallocchio
Istituto di Chimica Biomolecolare, CNR-Consiglio Nazionale delle Ricerche , Sassari, 07100 Li Punti Italy.
Alessandro
A
Dessì
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.
Mauro
M
Carcelli
Dipartimento di Chimica e Farmacia, Università di Sassari , Via Vienna 2, 07100 Sassari, Italy.
Vanna
V
Sanna
Dipartimento di Chimica e Farmacia, Università di Sassari , Via Vienna 2, 07100 Sassari, Italy.
Mario
M
Sechi
Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Lieve
L
Naesens
Influenza virus PA endonuclease; PA inhibitors (PAIs); dihydroxy-1H-indole-2-carboxamides; metal chelation; pharmacophore−structure virtual screening; polymerase