Towards a species-selective acetylcholinesterase inhibitor to control the mosquito vector of malaria, Anopheles gambiae.
Anopheles gambiae is the major mosquito vector of malaria in sub-Saharan Africa. At present, insecticide-treated nets (ITNs) impregnated with pyrethroid insecticides are widely used in malaria-endemic regions to reduce infection; however the emergence of pyrethroid-resistant mosquitoes has significantly reduced the effectiveness of the pyrethroid ITNs. An acetylcholinesterase (AChE) inhibitor that is potent for An. gambiae but weakly potent for the human enzyme could potentially be safely deployed on a new class of ITNs. In this paper we provide a preliminary pharmacological characterization of An. gambiae AChE, discuss structural features of An. gambiae and human AChE that could lead to selective inhibition, and describe compounds with 130-fold selectivity for inhibition of An. gambiae AChE relative to human AChE.
Carlier
Paul R
PR
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA. pcarlier@vt.edu
Anderson
Troy D
TD
Wong
Dawn M
DM
Hsu
Danny C
DC
Hartsel
Joshua
J
Ma
Ming
M
Wong
Eric A
EA
Choudhury
Ranginee
R
Lam
Polo C-H
PC
Totrov
Maxim M
MM
Bloomquist
Jeffrey R
JR
D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007303:Insect Vectors; D008288:Malaria / Q000635:transmission*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013045:Species Specificity
D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase