Target-Site Directed Herbicide Design

Abstract

The successful design of novel pesticides depends on careful consideration of a number of factors including target enzyme selection and validation, inhibitor design, delivery of the inhibitor to the target, and its metabolic fate. Strategies for the selection of enzyme targets giving the desired physiological response upon partial inhibition include identification of chemical leads, bacterial and plant conditionally lethal mutants and the use of antisense technology. Enzyme inhibitors having pharmaceutical or agrochemical utility can be categorized into six major groups: ground-state analogues, group specific reagents, affinity labels, suicide substrates, reaction intermediate analogues, and extraneous site inhibitors. Examples of each category, and their advantages and disadvantages, will be discussed. Identification of a target and construction of a potent inhibitor in itself may still not lead to an effective herbicide. In the absence of the desired invivo activity, the uptake, translocation, and metabolism of the inhibitor should be studied to assess the full potential of the target. Strategies for delivery of the compound to the target enzyme and avoidance of premature detoxification may include a proherbicidal approach, especially when inhibitors are highly charged or when selective detoxification or activation can be exploited. Utilization of differences in detoxification or activation between weeds and crops may lead to enhanced selectivity. Without a full appreciation of each of these facets of pesticide design, the chances for success with the target or enzyme-driven approach are reduced.