title: Identification and characterization of a dual-acting antinematodal agent against the pinewood nematode, Bursaphelenchus xylophilus.
abstract: The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+) channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.
authors.affiliation: Yonsei Proteome Research Center and Department of Biochemistry, College of Life Sciences and Biotechnology, WCU Program, Yonsei University, Seoul, Korea.
authors.forename: Wan-Suk
authors.initials: WS
authors.lastname: Oh
authors.forename: Pan-Young
authors.initials: PY
authors.lastname: Jeong
authors.forename: Hyoe-Jin
authors.initials: HJ
authors.lastname: Joo
authors.forename: Jeong-Eui
authors.initials: JE
authors.lastname: Lee
authors.forename: Yil-Seong
authors.initials: YS
authors.lastname: Moon
authors.forename: Hyang-Mi
authors.initials: HM
authors.lastname: Cheon
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Yong-Uk
authors.initials: YU
authors.lastname: Lee
authors.forename: Yhong-Hee
authors.initials: YH
authors.lastname: Shim
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Paik
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000969:Antinematodal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000235:genetics; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003433:Crosses, Genetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005821:Genetic Techniques; D009348:Nematoda / Q000378:metabolism*; D028223:Pinus / Q000378:metabolism* / Q000469:parasitology; D010935:Plant Diseases / Q000628:therapy*; D013997:Time Factors; D014197:Trees
chemical_list: D000935:Antifungal Agents; D000969:Antinematodal Agents; D002121:Calcium Channel Blockers