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Title: Inhibitor Profile of bis(n)-tacrines and N-methylcarbamates on Acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi

item SWALE, DANIEL - University Of Florida
item TONG, FAN - University Of Florida
item Temeyer, Kevin
item Li, Andrew
item LAM, POLO C-H - Molsoft, Llc
item TOTROV, MAXIM - Molsoft, Llc
item CARLIER, PAUL - Virginia Polytechnic Institution & State University
item Perez De Leon, Adalberto - Beto
item BLOOMQUIST, JEFFREY - University Of Florida

Submitted to: Pesticide Biochemistry and Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2013
Publication Date: 7/1/2013
Citation: Swale, D.R., Tong, F., Temeyer, K.B., Li, A.Y., Lam, P., Totrov, M.M., Carlier, P.R., Perez De Leon, A.A., Bloomquist, J.R. 2013. Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi. Journal of Pesticide Biochemistry and Physiology. 106:85-92.

Interpretive Summary: The southern cattle tick and the sand fly each feed on blood obtained from host animals. Both the tick and sand fly may acquire or transmit disease causing microorganisms during the process of obtaining blood from their host animals and are serious threats to animal and human health. One class of chemical acaricides and insecticides used to kill ticks, sand flies, and other pests works by inactivating an enzyme that is essential for function of the central nervous system of these pests. The enzyme targeted by this class of pesticides is called acetylcholinesterase. Research reported here utilized gene cloning to produce the tick and sand fly acetylcholinesterase enzymes in cell cultures so that the enzymes could be used to identify novel synthetic chemicals that worked better at inactivating the pest enzymes and may be safer to use than currently available pesticides.

Technical Abstract: The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAchE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE has low sensitivity (IC50 = 200 Micromolar) toward tacrine, a monovalent CS inhibitor with mid nanomolar blocking potency in all previous species tested. Similarly, a series of bis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency toward BmAChE. Molecular homology models suggest the rBmAChE enzyme possesses a W384F paralogous substitution near the catalytic site, where the larger tryptophan side chain obstructs the access of larger ligands to the active site. This finding suggests a unique AChE gorge structure in BmAChE, a phenomenon that can further support the possibility for design of selective inhibitors. In addition, BmAChE1 and PpAChE have low nanomolar sensitivity to a variety of experimental carbamate anticholinesterases we originally designed for control of the malaria mosquito, Anopheles gambiae. One experimental compound, 2-((2-ethylbutyl)thio)phenyl methylcarbamate, possesses >300-fold selectivity for BmAChE1 and PpAChE over human AChE, and a mouse oral LD50 of >1500 mg/kg, thus providing an excellent new lead for vector control.