title: Broad Spectrum Anti-Influenza Agents by Inhibiting Self-Association of Matrix Protein 1.
abstract: The matrix protein 1 (M1) of influenza A virus (IAV) exists as a three-dimensional oligomeric structure in mature virions with high sequence conservation across different IAV subtypes, which makes it a potential broad spectrum antiviral target. We hypothesized that impairing self-association of M1 through a small molecule 'wedge', which avidly binds to an M1-M1 interface, would result in a completely new class of anti-influenza agents. To establish this proof-of-principle, we performed virtual screening on a library of >70,000 commercially available small molecules that resulted in several plausible 'wedges'. Biophysical studies showed that the best molecule bound the M1 protein potently and weakened M1-M1 self-association. Most importantly, the agent reduced the thickness of the M1 layer in mature virions and inhibited in ovo propagation of multiple IAV strains including H1N1, pandemic H1N1, H3N2 and H5N1, which supports the "wedge" hypothesis. These results demonstrate that M1 is a promising druggable target for the discovery of a completely new line of broad spectrum anti-IAV agents.
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors: Philip D
authors: PD
authors: Mosier
authors: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors: Meng-Jung
authors: MJ
authors: Chiang
authors: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors: Zhengshi
authors: Z
authors: Lin
authors: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors: Yamei
authors: Y
authors: Gao
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors: Bashayer
authors: B
authors: Althufairi
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.|Department of Nanomedicine &Biopharmaceuticals, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Qibing
authors: Q
authors: Zhou
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors: Faik
authors: F
authors: Musayev
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors: Martin K
authors: MK
authors: Safo
authors: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors: Hang
authors: H
authors: Xie
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors: Umesh R
authors: UR
authors: Desai
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage*; D002460:Cell Line; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000472:pathogenicity; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000472:pathogenicity; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000890:Anti-Infective Agents; D000998:Antiviral Agents; C488936:M1 protein, Influenza A virus; D014763:Viral Matrix Proteins