title: Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers.
abstract: Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.
authors: Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA. samuel.gerritz@bms.com
authors: Samuel W
authors: SW
authors: Gerritz
authors: Christopher
authors: C
authors: Cianci
authors: Sean
authors: S
authors: Kim
authors: Bradley C
authors: BC
authors: Pearce
authors: Carol
authors: C
authors: Deminie
authors: Linda
authors: L
authors: Discotto
authors: Brian
authors: B
authors: McAuliffe
authors: Beatrice F
authors: BF
authors: Minassian
authors: Shuhao
authors: S
authors: Shi
authors: Shirong
authors: S
authors: Zhu
authors: Weixu
authors: W
authors: Zhai
authors: Annapurna
authors: A
authors: Pendri
authors: Guo
authors: G
authors: Li
authors: Michael A
authors: MA
authors: Poss
authors: Suzanne
authors: S
authors: Edavettal
authors: Patricia A
authors: PA
authors: McDonnell
authors: Hal A
authors: HA
authors: Lewis
authors: Klaus
authors: K
authors: Maskos
authors: Mario
authors: M
authors: Mörtl
authors: Reiner
authors: R
authors: Kiefersauer
authors: Stefan
authors: S
authors: Steinbacher
authors: Eric T
authors: ET
authors: Baldwin
authors: William
authors: W
authors: Metzler
authors: James
authors: J
authors: Bryson
authors: Matthew D
authors: MD
authors: Healy
authors: Thomas
authors: T
authors: Philip
authors: Mary
authors: M
authors: Zoeckler
authors: Richard
authors: R
authors: Schartman
authors: Michael
authors: M
authors: Sinz
authors: Victor H
authors: VH
authors: Leyva-Grado
authors: Hans-Heinrich
authors: HH
authors: Hoffmann
authors: David R
authors: DR
authors: Langley
authors: Nicholas A
authors: NA
authors: Meanwell
authors: Mark
authors: M
authors: Krystal
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D057446:Hydrodynamics; D051379:Mice; D008958:Models, Molecular; D009698:Nucleoproteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D009975:Orthomyxoviridae / Q000187:drug effects / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000627:therapeutic use; D012996:Solutions; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009698:Nucleoproteins; D054852:Small Molecule Libraries; D012996:Solutions