Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Curr Drug Targets. 2012 Apr;13(4):471-82. doi: 10.2174/138945012799499703.
Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the 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 insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market.
昆虫是全世界范围内导致人类痛苦和经济损失的罪魁祸首。为了应对这些严重的问题，我们急需新型的、环境友好的杀虫剂。目前杀虫剂的抗药性导致虫害再次猖獗，同时人们对杀虫剂毒性的担忧日益增加，这也阻碍了杀虫剂在害虫防治方面的应用。杀虫剂市场规模较小，这也限制了杀虫剂的发展；然而，基因组学和结构基因组学的进步为开发对杀虫剂市场依赖性较小的杀虫剂提供了新的机会。本文综述了文献数据，这些数据支持了这样一种假设，即位于乙酰胆碱酯酶活性部位开口处的昆虫特异性半胱氨酸残基是开发具有降低非靶标毒性和低昆虫抗性倾向的新型杀虫剂的有前途的靶标位点。这些数据用于讨论从降低非靶标毒性和昆虫抗性的角度，针对昆虫特异性半胱氨酸残基和乙酰胆碱酯酶普遍存在的催化丝氨酸残基的差异。本文还讨论了开发针对半胱氨酸的乙酰胆碱酯酶抑制剂作为有效且环境安全的杀虫剂，用于控制病媒、作物损害和住宅害虫，同时在当前杀虫剂市场的经济限制范围内。
