Computation-guided discovery of influenza endonuclease inhibitors.
Influenza is a global human health threat, and there is an immediate need for new antiviral therapies to circumvent the limitations of vaccination and current small molecule therapies. During viral transcription, influenza incorporates the 5'-end of the host cell's mRNA in a process that requires the influenza endonuclease. Based on recently published endonuclease crystalized structures, a three-dimensional pharmacophore was developed and used to virtually screen 450,000 compounds for influenza endonuclease inhibitors. Of 264 compounds tested in a FRET-based endonuclease-inhibition assay, 16 inhibitors (IC50<50 μM) that span 5 molecular classes novel to this endonuclease were found (6.1% hit rate). To determine cytotoxicity and antiviral activity, subsequent cellular assays were performed. Two compounds suppress viral replication with negligible cell toxicity.
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, 92093. USA.
Eric
E
Chen
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, 92093. USA.
Robert V
RV
Swift
Department of Pathology, University of California San Diego, La Jolla, California, 92093. USA.
Nazilla
N
Alderson
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, 92093. USA.
Victoria A
VA
Feher
Department of Pathology, University of California San Diego, La Jolla, California, 92093. USA.
Gen-Sheng
GS
Feng
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, 92093. USA.
Rommie E
RE
Amaro
Antiviral; endonuclease; influenza A; pharmacophore; virtual screening