title: The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma.
abstract: Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma.
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, G12 8TA, Glasgow, United Kingdom.
authors.forename: J C
authors.initials: JC
authors.lastname: Coltherd
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, G12 8TA, Glasgow, United Kingdom.
authors.forename: D T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, G12 8TA, Glasgow, United Kingdom.
authors.forename: R E
authors.initials: RE
authors.lastname: Lawrie
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, G4 0RE, Glasgow, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Al-Riyami
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, G1 1XL, Glasgow, United Kingdom.
authors.forename: C J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, G4 0RE, Glasgow, United Kingdom.
authors.forename: W
authors.initials: W
authors.lastname: Harnett
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, G12 8TA, Glasgow, United Kingdom.
authors.forename: M M
authors.initials: MM
authors.lastname: Harnett
mesh_terms: D056151:Airway Remodeling; D000485:Allergens / Q000276:immunology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015801:Helminth Proteins / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D018927:Anti-Asthmatic Agents; D016207:Cytokines; C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D007155:Immunologic Factors; D018836:Inflammation Mediators