title: Spiromastilactones: A new class of influenza virus inhibitors from deep-sea fungus.
abstract: A new class of phenolic lactones with trivial names of spiromastilactones A-M (1-13) was isolated from a deep-sea derived Spiromastix sp. fungus. Their structures featured by various chlorination at aromatic rings were determined on the basis of extensive spectroscopic analyses. An antiviral assay revealed that most of the tested compounds exert inhibitory activity against WSN influenza virus with low cytotoxicity, while the structure-activity relationships were discussed. Spiromastilactone D (4), a 5'-chloro-2'-methoxy substituted analogue, displayed the most potent to inhibit a panel of influenza A and B viruses in addition to drug-resistant clinical isolates. Mechanistic investigation resulted in that compound 4 bonded to hemagglutinin protein (HA), potentially at the spherical head, and disrupted the HA-sialic acid receptor interaction, that is essential for the attachment and entry of all influenza viruses. In addition, compound 4 also showed inhibitory effect toward viral genome replication via targeting viral RNP complex. The synergistic effects of 4 on both viral entry and replication assumed it to be a promising lead for the development of a new influenza inhibitor.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China; Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, SOA, Xiamen, 361005, PR China.
authors.forename: Siwen
authors.initials: S
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
authors.forename: Longlong
authors.initials: L
authors.lastname: Si
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, SOA, Xiamen, 361005, PR China.
authors.forename: Zongze
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, United States.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China. Electronic address: deminzhou@bjmu.edu.cn.
authors.forename: Demin
authors.initials: D
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China. Electronic address: whlin@bjmu.edu.cn.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry*; D001572:Benzofurans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D009980:Influenza A virus / Q000187:drug effects*; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D008826:Microbial Sensitivity Tests; D020036:Onygenales / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D007783:Lactones; C000611428:spiromastilactone D
keywords: Antiviral effect; Influenza virus; Marine-derived fungus; Mechanistic investigation; Spiromastilactones; Spiromastix sp.