Molecular pharmacology of new anticholinesterases for control of the malaria mosquito, Anopheles gambiae

There is an urgent need for additional insecticides to control the spread of malaria and other diseases. Recent advances in the molecular physiology of Torpedo californica acetylcholinesterase (AChE), finds an active site gorge leading to the catalytic site, adjoining an oxyanion hole. This enzyme also contains the so-called “peripheral site” that is near the external mouth of the gorge. In rat, this site and the catalytic site interact simultaneously with bivalent tacrines, potent inhibitors of mammalian AChEs. We have undertaken a systematic screening of bivalent tacrines having methylene linkers from 2-12 carbons in length in order to serve as “molecular rulers” of the distance between the catalytic and peripheral sites. In human, the optimum tether length is 7 carbons (IC50=1.6 nM), while in Anopheles gambiae, there is an optimum length at 4 carbons (IC50=163 nM). While these compounds are less potent and display less tether length dependency at Anopheles AChE, compared to human or rat, they do have significant activity against a G119S mutant of AChE that is highly resistant to many standard anticholinesterases. Classical inhibitors display little selectivity for insect vs. human forms of the enzyme AChE, typically < 4-fold. Recent results from this project have identified carbamate compounds having >100-fold selectivity for the malaria mosquito AChE compared to human AChE. These new molecules have unprecedented potential as leads to safe, effective mosquitocides in the fight against malaria.