title: Dual protonophore-chitinase inhibitors dramatically affect O. volvulus molting.
abstract: The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode's developmental process.
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Nancy
authors.initials: N
authors.lastname: Tricoche
authors.forename: Sara
authors.initials: S
authors.lastname: Lustigman
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000627:therapeutic use*; D017173:Caenorhabditis elegans / Q000378:metabolism; D002688:Chitinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D007476:Ionophores / Q000627:therapeutic use*; D018978:Molting / Q000187:drug effects; D017181:Onchocerca volvulus / Q000187:drug effects / Q000254:growth & development*; D009855:Onchocerciasis / Q000188:drug therapy; D012458:Salicylanilides / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014475:Uncoupling Agents / Q000627:therapeutic use
chemical_list: D000969:Antinematodal Agents; D004791:Enzyme Inhibitors; D007476:Ionophores; D012458:Salicylanilides; D014475:Uncoupling Agents; D002688:Chitinases; C023342:closantel