Biology Department Seminar

Insect pests are responsible for human suffering and financial losses worldwide. Resistance to current insecticides and reduced use of insecticides due to toxicity to humans have resulted in a resurgence of mosquito-borne diseases such as malaria. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Botulinum neurotoxin serotype A (BoNTA) causes life-threatening botulism. If used in an act of bioterrorism, BoNTA could afflict large, unprotected populations. It can also cause food or accidental clinical poisoning. Current treatment for BoNTA intoxication uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Small-molecule inhibitors of BoNTA are desirable because such molecules can be designed to enter cells to neutralize the intracellular toxin and offer post-exposure prophylaxis complementary to the antibody therapies. This presentation outlines (1) the multidisciplinary studies on target identification and lead discovery that support our hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insecticide resistance[1] and (2) the in silico to in vivo studies of our small-molecule BoNTA inhibitors that are designed via computer simulations to selectively inhibit the zinc-embedded active site of the BoNTA endopeptidase and have shown post-exposure protection of vertebrates against supralethal BoNTA[2-5]. 1. Pang, Y.-P., et al. Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides. Curr Drug Targets 13, 471-482 (2012), open access. 2. Park, J. G. et al. Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A. Bioorg. Med. Chem. 14, 3