Targeting Voltage-Gated Sodium Channels for Insect Control: Past

Chapter 3

Targeting Voltage-Gated Sodium Channels for Insect Control: Past, Present, and Future Downloaded by COLUMBIA UNIV on October 31, 2017 | http://pubs.acs.org Publication Date (Web): October 24, 2017 | doi: 10.1021/bk-2017-1264.ch003

David M. Soderlund* Department of Entomology, Cornell University, Geneva, New York 14456, United States *E-mail: [email protected].

Voltage-gated sodium channels play a fundamental role in neuronal signaling. The crucial importance of sodium channels is evident in the great structural and pharmacological variety of naturally-occurring neurotoxins produced by plants, animals and microorganisms that disrupt channel function, thereby contributing to the chemical warfare of predation and defense. The importance of sodium channels as insecticide targets was first established by the discovery of the natural insecticide pyrethrum more than two centuries ago. Since then, the empirical search for new insecticidal agents has "rediscovered" the sodium channel as a target many times, exploiting not only the receptor site for pyrethrum constituents and their synthetic analogs, the pyrethroids, but also other receptor sites on the sodium channel protein. Here I reflect on the history of sodium channel exploitation for insect control and the current status of sodium channel-directed insecticides, and I consider the durability of sodium channels as targets for the continued development of insect control agents.

Voltage-Gated Sodium Channels Voltage-gated sodium channels (VGSCs) are both ubiquitous and essential (1). They are located in the cell membranes of neurons and vertebrate skeletal and cardiac muscle, where they play critical roles in electrical signaling. Sodium channels open transiently in response to changes in the electrical potential across © 2017 American Chemical Society Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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the cell membrane, allowing sodium ions to flow into the cell. The resulting transient depolarization underlies the nerve or muscle action potential. The essential functions of VGSCs are intrinsic to a single, large, conformationally flexible transmembrane protein (the α subunit) that forms a sodium-selective ion pore (2). The structures of VGSC α subunits are highly conserved across the animal kingdom, especially in the 24 transmembrane helices and four pore-forming loops. In this regard, VGSCs differ from ligand-gated ion channels (i.e., neurotransmitter receptors). Ligand-gated ion channels are heteromultimers composed of various combinations of subunit proteins that are less conserved, at the amino acid sequence level, than VGSC α subunits. Insects and vertebrates have taken different routes to achieving functional diversity of VGSCs in different cells and tissues and at different developmental stages. In insects VGSCs are encoded by a single gene (para in Drosophila melanogaster and its orthologs in other species) that undergoes alternative splicing and RNA editing at multiple sites to yield a large theoretical number of splice and editing variants, not all of which are found in surveys of mRNA diversity (3). The functional characterization of splice variants isolated from a single species confirmed that alternative splicing yields VGSCs with different functional properties. Additional functional diversity may be conferred by coexpression in the cell membrane of the VGSC α subunit with one of a family of small auxiliary subunits. By contrast, VGSC α subunits in mammals comprise a family of nine isoforms (designated Nav1.1 – Nav1.9) that exhibit unique patterns of developmental and anatomical expression and varied functional and pharmacological properties (2). Mammalian VGSC α subunits are highly conserved among themselves (>90% amino acid identity). Additional heterogeneity among sodium channels expressed in vivo results from their coassembly in the nerve membrane with one or two small auxiliary β subunit proteins, which are structurally unrelated to the auxiliary subunits of insect VGSCs.

Coevolutionary Exploitation of Sodium Channels Sodium channels are the site of action of a large structural variety of naturally-occurring neurotoxins (4, 5). This coevolutionary convergence of strategies for chemical predation and defense on a single protein underscores both the fundamental significance of VGSCs in the normal function of animal nervous systems and the disruptive potential of agents that modify normal VGSC function. The sites of action of these neurotoxins, identified in functional and radioligand binding assays and by site-directed mutagenesis, identify seven distinct binding domains for naturally-occurring neurotoxins on the VGSC α-subunit protein (Table 1). These binding sites are operationally defined by competitive interactions among toxins considered to act at the same domain and allosteric interactions between toxins acting at different domains. However, different residues in the sodium channel protein may be critical for the binding of different ligands that compete for occupancy of same binding domain. Moreover, 38 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

additional neurotoxins not shown in Table 1 modify VGSC function by action at binding domains that are distinct from Sites 1-7 but otherwise incompletely characterized.


Table 1. Neurotoxin Binding Sites on Voltage-Gated Sodium Channelsa

a

Site

Active Neurotoxins

Physiological Effect

1

Tetrodotoxin Saxitoxin μ-Conotoxins

Pore block

2

Veratridine Batrachotoxin Aconitine Grayanotoxins

Persistent activation Depolarization of resting potential Repetitive nerve firing

3

α-Scorpion toxins Sea anemone toxins δ-Astracotoxins

Prolonged channel opening

4

β-Scorpion toxins

Shifts in activation gating Repetitive nerve firing

5

Brevetoxins Ciguatoxins

Shifts in activation gating

6

δ-Conotoxins

Prolonged channel opening

7

Pyrethrins

Persistent activation Depolarization of resting potential Repetitive nerve firing

Sites 1-6 after Catterall et al. (4); Site 7 assigned arbitrarily as distinct from Sites 1-6.

With the exception of compounds acting at Site 1, all of the neurotoxins listed in Table 1 modify VGSCs to increase the probability or persistence of channel opening; the resulting enhanced influx of sodium ions causes neuronal excitation and results in aberrant neural signalling. These effects are particularly powerful because they disrupt nerve function at neurotoxin concentrations that modify only a small fraction of the available sodium channels; these toxins are therefore much more potent that would be expected based on conventional indices of pharmacological potency, which are based on concentrations producing half-maximal effects.

Sodium Channel-Directed Insecticides: Past and Present Pyrethrum The initial "discovery" of the VGSC as an insecticide target site occurred more than two centuries ago with the observation that dried pyrethrum flowers (Tanacetum cinerareaefolium) killed insects (6). In the 19th century insecticidal pyrethrum powder was widely available and used in Europe and Asia and was 39 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


imported into the United States as early as 1860. During the early decades of the 20th century pyrethrum (an organic extract of pyrethrum flowers) was produced commercially and widely used for insect control despite its expense and lack of environmental persistence. The introduction of more stable and less expensive synthetic insecticides limited the use of pyrethrum-based products, but pyrethrum is still produced commercially, registered for use, and remains an valuable insecticide option where low residual activity is important as well as in organic production. Pyrethrum was used widely as an insecticide long before the structures of its insecticidal constituents were known. The iterative application of newly-available methods and tools in natural products chemistry eventually identified six structurally-related esters, collectively called the pyrethrins (Figure 1) (7). Of these, pyrethrins I and II are the most abundant and typically exhibit the highest insecticidal activity. The extremely rapid action of pyrethrum on insects pointed to an effect on the nervous system. Early electrophysiological studies of the action of pyrethrins on invertebrate neurons using extracellular electrodes identified a consistent pattern of initial hyperexcitation, characterized by bursts of spontaneous and evoked action potentials, followed by nerve block (8). There is little further information on the mode of action of pyrethrins, either as a mixture of esters or as individual components. Therefore, much of what we infer about the action of pyrethrins is based on more detailed studies with allethrin, a close structural analog of pyrethrin I (Figure 2). Detailed voltage-clamp studies in both invertebrate and vertebrate axon preparations showed that allethrin modifies nerve membrane sodium currents by prolonging the opening of voltage-gated sodium channels. These findings established the voltage-gated sodium channel as the principal target site not only for allethrin but also, by inference, for the pyrethrins (8).

Figure 1. Structures and nomenclature of the pyrethrins. 40 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 2. S-bioallethrin.

DDT From our 21st century perspective it is difficult to appreciate the magnitude of the revolution in insect control afforded by DDT. Before DDT, chemical control of insect pests depended on inorganic compounds and natural products of botanical origin (including pyrethrum) (9). All of these agents were limited in effectiveness by their cost, performance or availability. DDT provided, for the first time in human history, relatively cheap and highly effective control of a broad spectrum of insect pests and disease vectors. The legacy of DDT, viewed from today’s perspective, is ambiguous (10). DDT not only protected crops but also saved lives; its use by the World Health Organization to control the mosquito vectors of malaria came very close to eradicating this disease before its use was curtailed. The success of DDT stimulated the search for new synthetic insecticides, which ultimately resulted in the array of highly effective insect control agents that are available today. However, the success of DDT also contributed to its downfall. In the 1950s and 1960s more than a billion tons of DDT were used in U.S. agriculture. The selection for resistance in populations of major pests led to increased use rates. The environmental persistence of DDT, initially viewed as a benefit allowing efficient control of insects, led to bioaccumulation in the environment and effects on nontarget species. In this way DDT contributed to the birth of the environmental movement and the creation of the U.S. Environmental Protection Agency, which in turned banned all uses of DDT in 1972. From the perspective of this review, the most significant aspect of DDT’s success as an insecticide lies in its validation of the voltage-gated sodium channel as a premier target for insect control agents (11). Early studies of the action of DDT on invertebrate neurons identified effects that were qualitatively similar to those of pyrethrins, and subsequent voltage-clamp experiments showed that DDT and allethrin modified sodium currents in nerve axons in a similar manner. The discovery of house fly strains resistant to both DDT and the rapid paralytic effects of pyrethrins provided further evidence for a shared mode of action. In the past two decades, genetic and molecular analyses of knockdown resistance in flies and other invertebrates have provided convincing evidence that mutations in genes encoding sodium channel α subunits underlie this type of resistance (12–14). 41 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Pyrethroids The synthetic pyrethroids were developed over several decades by the iterative replacement of structural elements of the natural pyrethrins with other elements that preserved the steric and electronic features of the parent molecules (15, 16). The first breakthrough from this effort was the discovery of resmethrin (Figure 3) (17). Resmethrin surpassed both the pyrethrins and earlier synthetic analogs (e.g., allethrin; Figure 2) in both insecticidal activity and safety to mammals, but it remained susceptible to photochemical degradation and was therefore just as unstable in light and air as the pyrethrins and earlier synthetic compounds. Efforts to retain the favorable insecticidal and toxicological properties of resmethrin but improve environmental stability sufficiently to permit use in agricultural applications led, in the early 1970s, to the discovery of permethrin, deltamethrin and fenvalerate (Figure 3), the first pyrethroids developed for agricultural use (18). By 1995, more than 20 synthetic pyrethroids had been developed and registered for use worldwide (9).

Figure 3. Structures of resmethrin, permethrin, deltamethrin and fenvalerate. Pyrethroids proved to be surprisingly durable despite the impact of resistance in many important pest populations and the subsequent introduction of competing insect control technologies (Figure 4). Prior to the discovery of permethrin, deltamethrin and fenvalerate the commercial use of pyrethroids was insignificant, but by the late 1980s use of these compounds had grown to represent nearly 20% of the world insecticide market (19, 20). The introduction of commercial varieties of transgenic Bt cotton in the mid-1990s marked the beginning of a decline in pyrethroid use as transgenic cotton reduced the use of pyrethroids on that crop. Nevertheless, in 2013 still represented 17% of total insecticide sales worldwide (21). Pyrethroids disrupt nerve function by binding to a receptor site (Table 1, Site 7) that was first identified by the action of pyrethrins and subsequently also by the action of DDT (22). Different structural classes of pyrethroids produce qualitatively different effects depending on the duration of the pyrethroid-modified open state. Pyrethroids may also bind preferentially to either the resting (closed) 42 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


or the open state of the channel, depending on the pyrethroid and sodium channel preparation examined. The identification of pyrethroid resistance-associated mutations sodium channel genes and the functional characterization of wildtype and mutated channels in vitro have defined sodium channel domains that are determinants of pyrethroid sensitivity. More recently, this information has been employed to construct high-resolution structural models of the interaction of pyrethroid insecticides and DDT with these domains (12).

Figure 4. Pyrethroid use, measured as percent of the U.S. dollar value of worldwide sales, from 1972 to 2013 (19–21).

Sodium Channel Inhibitors Research at Philips-Duphar in the early 1970s identified novel substituted pyrazolines (PH-60-41, PH-60-42; Figure 5) with excellent insecticidal activity and signs of intoxication consistent with an action on the nervous system (23). Poor photostability and high soil persistence prevented the development of commercial products from this series. More than a decade later, Rohm and Haas reported the discovery of a second generation of pyrazoline-derived insecticides, exemplified by RH3421 (Figure 5) (24). These compounds retained the excellent insecticidal activity of the earlier pyrazolines but exhibited improved photostability and reduced environmental persistence. 43 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 5. Structures of early pyrazoline-based insecticides.

The development of commercial insecticide products from the pyrazoline series was ultimately halted by their high mammalian toxicity (25). Although the single-dose oral acute toxicity of these compounds was very low, longer-term dietary feeding studies revealed a delayed-onset acute neurotoxic response that occurred at doses lower than those producing acute intoxication following a single oral dose. Research to modify the core ring structure of the pyrazolines eventually yielded the first commercial insecticides from this group. Indoxacarb, an oxadiazine-based compound (Figure 6), was the first insecticide derived from the pyrazoline series to achieve commercial registration (26). Indoxacarb is a proinsecticide that is selectively hydrolyzed in insects to yield the ultimate toxicant, DCJW (Figure 6). The selective bioactivation of indoxacarb underlies its favorable selective toxicity and overcomes the toxicological barriers that were inherent in the pyrazoline series. Complete replacement of the central nitrogen-containing ring structure of the pyrazolines and the indoxacarb series led to the discovery of metaflumizone (Figure 6), the most recently-commercialized compound of this class (27).

Figure 6. Structures of indoxacarb, its bioactivation product DCJW, and metaflumizone. 44 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Compounds identified as sodium channel inhibitors (SCIs; also called sodium channel blockers), though structurally diverse, are unified by a conserved core structure (Figure 7) (27) and a common mode of action on voltage-gated sodium channels (28). SCIs bind preferentially to sodium channels in the slow-inactivated state, a non-conducting conformational state that results from prolonged or repetitive depolarization (Figure 8). This interaction is very stable, resulting in the formation of a pool of insecticide-bound nonconducting channels and reducing the number of resting channels available for activation. The progressive sequestration of channels in the insecticide-stabilized slow-inactivated state eventually results in nerve block.

Figure 7. A proposed common core structure of SCI insecticides.

Figure 8. Conceptual model of the state-dependent action of SCI insecticides, illustrating the interconversion of channels in the closed (C),open (O), fast-inactivated (Ifast), and slow-inactivated (Islow) states. Site-directed mutagenesis studies showed that the SCI binding domain is likely to exist at the inner pore of the sodium channel protein, where it shares common molecular determinants with the binding site for local anesthetic and antiarrhythmic drugs (28). This site is distinct from the seven neurotoxin-binding domains on the channel protein (Table 1), and therefore represents a novel site and mechanism of insecticide action on sodium channels distinct from those identified for pyrethrins, pyrethroids and DDT. 45 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Current Status of Sodium Channel-Directed Insecticides Figure 9 summarizes the relative importance, measured as worldwide sales, of different insecticide classes as reported by Sparks in 2013 (21). Compounds acting on ion channel targets accounted for approximately two-thirds of the insecticide market, with sodium channel-directed compounds (pyrethroids and SCIs) representing 19% of sales. Going forward, it is not clear whether the relative importance of sodium channel-directed insecticides will increase, remain stable or decrease. Pyrethroid use appears to be in a slow downward trend (see Figure 4) and the two commercially-available SCIs represent only a small segment of the market. However, the current regulatory pressure on neonicotinoid insecticide use may affect the future importance not only of sodium channel-directed compounds but also compounds acting at other targets.

Figure 9. Insecticide use by chemical class and target site, measured as total sales reported in 2013.

Future Sodium Channel-Directed Insecticides? The extensive exploitation of VGSCs for insect control by pyrethrum, DDT, and pyrethroids, together with widespread selection for target site-mediated resistance, might suggest that there is little future for the development of new insecticides acting at this target. However, the central importance of VGSCs in the processes underlying undesirable or damaging insect behaviors, the success of past and current insecticides acting at this target, and the rich pharmacology of the VGSC (Table 1) all argue for a role of VGSCs in future insect control, either by targeting currently-unexploited sodium channel binding sites or by the discovery of new target domains on the sodium channel protein. 46 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Targeting Unexploited Binding Sites Of the seven discrete, well-characterized neurotoxin binding domains on the VGSC α subunit (Table 1), only one (Site 7) has been heavily exploited for insect control. Insecticidal agents acting at other receptor domains are likely to be unaffected by the domain-specific resistance limiting the action of insecticides acting at Site 7. The potential for this approach is illustrated by the discovery of novel isobutylamide insecticides that act at VGSC Site 2. The medicinal and insecticidal properties of naturally-occurring unsaturated aliphatic isobutylamides have been known since the early 19th century (29). Pellitorine (Figure 10), the earliest well-characterized example of this class, is the insecticidal principle isolated from the roots of Anacyclus pyrethrum. Pipercide (Figure 10), isolated from Piper nigrum, exemplifies naturally-occurring isobutylamides with extended aliphatic chains and aromatic substituents that exhibit greater insecticidal activity than pellitorine. Synthetic optimization from these natural product templates yielded compounds (e.g., BTG 502, Figure 10) with improved insecticidal activity (30). Moreover, BTG 502 was more effective against housefly strains carrying the super-kdr trait that confers high levels of pyrethroid resistance than against wildtype strains.

Figure 10. Structures of natural and synthetic isobutylamide insecticides.

47 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


In electrophysiological studies with insect nerve preparations, insecticidal isobutylamides induced repetitive activity followed by conduction block in housefly nerves, induced persistent sodium tail currents in cultured locust neurons, and inhibited the veratridine-dependent release of acetylcholine from cockroach presynaptic nerve terminals. These results pointed to an action on VGSCs that was qualitatively similar to that of pyrethroids but did not identify which sodium channel binding domain served as the isobutylamide target. More detailed pharmacological studies using mouse brain preparations and assays of radiosodium uptake and radioligand binding showed that BTG 502 and related insecticidal compounds acted as partial agonists at VGSC Site 2, thus identifying a novel insecticide target domain on the VGSC. Analysis of the pharmacological impact of point mutations introduced into insect sodium channels suggest that the binding site for pyrethroids and BTG 502 lie in close proximity to each other (31). Insecticidal isobutylamides have so far proved to be too unstable in the environment for commercial development. Nevertheless these compounds illustrate the potential for the discovery of new insecticides acting at sodium channel domains other than Site 7 that are not affected by resistance mechanisms that selectively alter the sensitivity of insect VGSCs to pyrethroids.

Discovering New Binding Sites The list of neurotoxin receptor sites on the VGSC (Table 1) is not finite. The discovery and exploitation of the local anesthetic receptor domain, first by drugs and more recently by SCI insecticides, illustrate the potential for the discovery of new chemistry that targets VGSCs by binding to previously-unrecognized receptor domains on the large VGSC protein. The most straightforward way to search for new agents that act at the VGSC would be to screen chemical libraries against insect VGSCs in vitro, specifically looking for compounds that function as sodium channel activators and are not affected by mutations that reduce the sensitivity of channels to pyrethroids. It would also be possible to counter-screen initial leads against human sodium channels in vitro to identify compounds with intrinsic selective toxicity to insects. Although attractive in principle there are two significant challenges inherent in this approach. First, to date insect sodium channels have been expressed in vitro only in the Xenopus laevis oocyte system (3). Although the automated high-throughput screening of channels expressed in oocytes is feasible, it remains more cumbersome that the use of stably-transformed cell lines as screening substrates. Further, we now know that the cellular environment of the oocyte expresses VGSCs with different functional and pharmacological properties than channels in cell lines or native neurons. For example, the actions of pyrethroids on rat Nav1.6 sodium channel complexes expressed in oocytes differ markedly from the actions of the same compounds on the identical channel complexes expressed in stably-transformed HEK293 cells when assayed under comparable voltage clamp conditions (32). Moreover, the properties of channels expressed in HEK293 cells, but not in oocytes, are similar to the functional and pharmacological properties of VGSCs expressed in mammalian neurons. 48 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Therefore, in vitro screens for novel agents acting on insect VGSCs would benefit greatly from the development of stable cell lines expressing insect VGSCs. The second challenge to the in vitro screening approach is more generic. Intrinsic activity against a desirable target in vitro may be difficult to translate into compounds that can provide effective insect control in the real world and also exhibit environmental and toxicological profiles that will permit their development. These challenges are well illustrated by the current range of insecticidal compounds that act on sodium channels, all of which were identified by conventional screens for insecticidal action. The development or use of these compounds has been impeded or prevented by unacceptable persistence (either too short or too long) in the environment (e.g., pyrethrins, DDT, SCIs, isobutylamides) or toxicity to nontarget organisms (e.g., DDT, SCIs). In some cases these impediments were overcome to yield successful insecticides, but in other cases they prevented either continued use or commercial development. It is more likely that new insecticides that act at previously-unknown receptor domains on the VGSC will be identified the old-fashioned way – by empirical screening for insecticidal activity, followed by determination of mechanism of action. The essential function and the rich pharmacology of the VGSC suggest that screens for compounds that rapidly and irreversibly alter undesirable behaviors in pest insects will continue to identify compounds that act at the VGSC, and some of these compounds will likely be found to define new binding domains on the channel protein. The advances of the past two decades in the understanding the structure, function, and pharmacology of VGSCs at the molecular level will accelerate the further development of these novel compounds.

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Targeting Voltage-Gated Sodium Channels for Insect Control: Past

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