Development and Evaluation of an Immunological Approach for the Identification of Novel Acetyl Coenzyme-A Carboxylase Inhibitors:  Assay Optimization and Pilot Screen Results

Abstract

Cyclohexanediones, aryloxyphenoxypropionates, indolizidinediones, and triazinediones are four known structural classes of herbicides that inhibit acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2). An immunological study to determine the potential of ACCase inhibitor-specific monoclonal antibodies as screening tools to identify novel lead chemistry was undertaken. Using two cyclohexanedione-specific monoclonal antibodies (mAb A and mAb B; Webb, S. R.; Hall, J. C. J. Agric. Food Chem. 2000, 48, 1210-1218) and three different cyclohexanedione hapten coating conjugates, competitive indirect enzyme-linked immunosorbent assays (ciELISA) were developed. Cross-reactivity of the monoclonal antibodies with four structural classes of ACCase inhibitors revealed that the ciELISA using mAb A and a modified cyclohexanedione hapten coating conjugate detected analogues from all four known classes of ACCase inhibitors. A pilot screen using this ciELISA format identified two novel ACCase inhibitors, demonstrating the potential for antibodies as rapid and cost-effective screening tools for identifying novel lead chemistry in pesticide discovery programs.

Weed resistance to acetyl coenzyme A carboxylase inhibitors: an update

“…Another approach involves high-throughput, random screening of molecules for anti-ACC activity. In the absence of a microassay for ACC activity, a pilot screen that uses antibody mimics of homomeric ACCs to identify such molecules has been developed (Webb and Hall 2002). In contrast to this approach, the availability of the tridimensional structure of the CT domain of homomeric ACC (Zhang et al 2003) should enable the rational design of ACC inhibitors.…”

Synthesis of Ligand-Specific Phage-Display ScFv against the Herbicide Picloram by Direct Cloning from Hyperimmunized Mouse

“…The versatility and flexibility of antibody (Ab) technology can be used in agriculture in numerous ways. Antibodies can be used in immunoassays to monitor agrochemicals in the environment for registration and stewardship purposes ( − ), in affinity chromatography for extraction and purification of ligands of interest (), and to screen potential lead chemistry for development of new drugs and pesticides ( − ). Production of recombinant Abs using phage-display technology has many advantages over conventional polyclonal and monoclonal Ab production ( 2 , 8 , 9 ).…”

Interaction of Cyclohexanediones with Acetyl Coenzyme-A Carboxylase and an Artificial Target-Site Antibody Mimic: A Comparative Molecular Field Analysis

“…In contrast, the steric graph of the antibody model ( Figure 7A) contained three small unfavorable steric regions (yellow), none of which corresponded to the size or location of the yellow region on the ACCase steric map ( Figure 6A). These differences in the location and size of the unfavorable steric regions (yellow) when the ACCase and antibody steric graphs are compared ( Figures 6A and 7A) may explain the differences in the response of mAb A and ACCase to analogue 25 (Table 1; Webb and Hall, 2000b).…”

“…These similarities may account for the qualitative relationship between cyclohexanedione inhibition of mAb A and ACCase. These similarities may also account for the ability of mAb A to cross-react with the other structural classes of ACCase inhibitors (Webb and Hall, 2000b). For example, Rendina et al (1995) suggested that the aryloxyphenoxypropanoic acid structural classes of ACCase inhibitors overlap through the oxime region of the cyclohexanediones.…”

“…The structures of the cyclohexanedione analogues and their corresponding inhibitory activity against both ACCase and the monoclonal antibody designated mAb A (Webb et al, 1997;Webb and Hall, 2000b) are shown in Figure 1 and Table 1, respectively. The initial 3D coordinates for the cyclohexanedione structures ( Figure 1 CoMFA Models for Cyclohexanedione Herbicides J.…”