|SWALE, DANIEL - University Of Florida|
|CARLIER, PAUL - Virginia Polytechnic Institution & State University|
|Perez De Leon, Adalberto - Beto|
|BLOOMQUIST, JEFFREY - University Of Florida|
|TOTROV, MAXIM - Molsoft, Llc|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/19/2012
Publication Date: N/A
Interpretive Summary: The cattle tick, Boophilus microplus, is a potentially deadly pest of cattle that vectors the infectious agents causing bovine babesiosis and anaplasmosis. Similarly, the sand fly, Phlebotomus papatasi, is a vector of the protozoa causing leishmaniasis in humans and animals. Organophosphates and carbamate pesticides kill ticks and flies by targeting the enzyme acetylcholinesterase in their central nervous system. The purpose of this study was to characterize the biochemical inhibitor profile of acetylcholinesterase (AChE) for these disease vectors for comparison to human AChE. Results indicate that the tick enzyme (BmAChE1) has uniquely low sensitivity to tacrine, an inhibitor with very high blocking potency in all previous species tested. Similarly, additional AChE inhibitors possess poor potency toward BmAChE1 further reveling biochemical properties unique to the tick enzyme. Molecular homology models suggest that amino acid substitutions unique to the tick enzyme structure prevent binding of inhibitors common to AChE of other species. This finding suggests that the ticks possess a unique AChE gorge structure, a characteristic that supports the design of novel tick-specific inhibitors. Secondly, results indicate that several experimental carbamate AChE inhibitors exhibit up to 350-fold selectivity for BmAChE1 and for the AChE of the sand fly over human AChE, providing new leads for development of novel control technology. One such compound exhibited very low oral toxicity for mice, strongly indicating that it is an excellent candidate for the development of a new pesticide specifically targeted to control these important disease vectors.
Technical Abstract: The cattle tick, Boophilus microplus, and the sand fly, Phlebotomus papatasi (Pp), are vectors of infectious agents affecting cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from R. microplus(BmAChE1) and Pp (PpAchE) for comparison to human and bovine AChE profiles to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE1 has uniquely low sensitivity (IC50 = 220 µM) toward tacrine, an inhibitor with nanomolar blocking potency in all previous species tested, including Phlebotomus papatasi. In addition, BmAChE1 and PpAChE have low nanomolar sensitivity to a variety of carbamate anticholinesterases. 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 >1000 mg/kg. This novel compound provides an excellent new lead for vector control compounds.