title: Novel selective and irreversible mosquito acetylcholinesterase inhibitors for controlling malaria and other mosquito-borne diseases.
abstract: We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (k(inact)/K(I)) of 3,604-458,597 M(-1)sec(-1) but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with k(inact)/K(I) values of 1,915 and 1,507 M(-1)sec(-1), respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.
authors: Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors: Dengfeng
authors: D
authors: Dou
authors: Jewn Giew
authors: JG
authors: Park
authors: Sandeep
authors: S
authors: Rana
authors: Benjamin J
authors: BJ
authors: Madden
authors: Haobo
authors: H
authors: Jiang
authors: Yuan-Ping
authors: YP
authors: Pang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D009033:Culicidae / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007700:Kinetics; D008288:Malaria / Q000517:prevention & control; D013058:Mass Spectrometry; D010261:Paraoxon / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D015800:Protozoan Proteins; D000110:Acetylcholinesterase; D010261:Paraoxon