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Norbormide is a uniquely selective rat toxicant for Rattus species, with rats being 100- to 150-fold more sensitive to norbormide toxicity than most other mammals and birds. Previously we reported that on completion of a 10-year program of targeted fundamental and applied synthetic chemistry and toxicology, taste aversion associated with this compound had been overcome. In 2020-2022, trials have been successfully completed on poultry farms with Norway rats and larger scale field trials were undertaken targeting ship rats using 1% norbormide paste baits. Firstly, the efficacy of norbormide-containing paste baits targeting rat infestations on poultry farms was proven with a 100% reduction of Norway rat populations on three different farms. Secondly, 100% reduction in ship rat abundance was achieved at two large field test sites; and no reduction was achieved at the untreated control site. These larger field trials are described in depth in this publication. Plans are progressing to complete product development and registration.

Field trials are reported in this paper on a new bait containing 1% norbormide. Two separate field trials were recently completed on commercial chicken farms in South Auckland, New Zealand. Norway rats were abundant both inside the farm sheds and around the surrounding farmland. Monitoring undertaken before toxic baiting recorded high levels of rat activity. Post-treatment monitoring found no rat paw prints in any of the tracking tunnels from Site 1, and in only one tunnel at Site 2. The decrease of 100% and 96%, respectively, represented a marked reduction in the Norway rat population at both sites.

Norbormide (NRB) is a Rattus-selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non-Rattus species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular KATP channels, which potentially controls its Rattus-selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable Rattus-selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications. [ABSTRACT FROM AUTHOR]

The history of discoveries in rodenticide development and control technology as well as current and future-focused research are explored. Traps and older poisons such as red squill, arsenic, and cyanide have been used for hundreds if not thousands of years. Between 1940 and 1980 there was a period of innovation with the discovery of new molecules, including acute toxins and slower acting anticoagulants. The period 1980 to 2018 has been a time for improved utilization of individual tools and research to retain registrations, develop new toxins and delivery systems, and explore non-lethal control options. However, despite these advances, decades old broad-spectrum toxins and traplines are still the mainstay of pest control. Technological leaps are needed to achieve much more precise, affordable, and socially acceptable pest control. The period 2018 to 2050 should be a time for accelerated innovation. There are exciting opportunities for transformational change based on the integration of existing and new tools, such as advances in automated species recognition systems, new self-resetting traps, and species-specific toxin-delivery systems. Over-reliance on 'silver bullet' technologies for small mammal pest control is the wrong approach to biodiversity conservation. This has been demonstrated through two decades of challenging research on viral vectored immunocontraception, and would apply if all pest control research focused on a single toxin, one new engineering-based technology, or on gene editing, which has potential, but will not be a panacea for all mammal pests. Balance is important, with research supporting the skill of pest control practitioners and supporting emerging technologies, as well as novel biocontrol or genetic research. There has been no focused research aimed at integrating a broad suite of new tools, and incorporating disruptive technologies from completely different fields. We believe that science and technology have now advanced such that automated, online, and real-time systems for monitoring and managing pests are achievable in the next decade.

Norbormide is a rat specific toxicant. It causes vasoconstriction of small arteries and vasodilation of large arteries in rats, which results in a rapid fall in blood pressure and death from heart failure. It is an extraordinary compound in that it is only toxic to rats. The lack of toxicity of this compound to birds and other mammals is unique. It was originally researched in the 1960s and initially marketed in the USA. Problems with taste aversion slowed its continued use and sales it and was largely forgotten when anticoagulant rodenticides became more effective and popular. Following the emergence of anticoagulant resistance in some populations of rodents, residues of the second-generation anticoagulants in wildlife and concerns regarding humaneness, interest in non-anticoagulants, such as norbormide, has revived. Research has been conducted to help identify and understand a formulation of norbormide which is palatable, effective, and fast acting in rats. Further research is underway to determine methods for large scale synthesis of an improved form of norbormide. Field trials are planned in 2018/19. The ability to target rats with no risk to non-target species presents considerable advantages in many settings and warrants further investment and completion of the current scale-up phase of research and development.

Internationally, over the last 20 years the number of tools available for the control of small mammals has declined. Through the efforts of research we have bucked this trend and retained and developed new tools. Three new toxins have been extensively researched and registered, namely para-aminopropiophenone (PAPP) in 2011 for stoats and feral cats; zinc phosphide for possums in 2012; and encapsulated sodium nitrite (ESN) in 2013, for possums and feral pigs. The development of PAPP and ESN, coined red blood cell toxins, developed for humaneness, represent the first new vertebrate pesticides registered for field control of mammalian pests anywhere in the world for >30 years. Research on rodenticides including diphacinone with the additive cholecalciferol (D+C) and a palatable form of norbormide continues. A New Zealand EPA application for D+C was filed in June 2015. More effective killing systems are being researched, and the first successful field trials of resetting toxin delivery devices for possum and stoat control were completed in 2013 and 2014. Improved deployment strategies, integration of humane and selective toxins, lures of greater potency, and improved killing devices aided by species’ recognition will transform ground control for endangered species protection. Sodium fluoroacetate (1080) and other important tools have been retained as new tools are emerging from a research and development pipeline. It is important for the future of New Zealand’s biodiversity that this focused research continues and we continue to learn and advance new technologies. Our goals are shifting to enable reduction in density of rat, stoat, and possum populations to zero over large scales (i.e., elimination at landscape scale), and to hold these at zero through detection and response, including the use of new technologies for perimeter control as part of barrier systems for conservation.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka (Leptospermum scoparium) nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation. Using gelatin zymography, 40 μg/mL LepteridineTM inhibited the gelatinase activities of both pro- (22%, p < 0.0001) and activated (59%, p < 0.01) MMP-9 forms. By comparison, LepteridineTM exerted modest (~10%) inhibition against a chromogenic peptide substrate and no effect against a fluorogenic peptide substrate. These findings suggest that LepteridineTM may not interact within the catalytic domain of MMP-9 and exerts a negligible effect on the active site hydrolysis of small soluble peptide substrates. Instead, the findings implicate fibronectin II domain interactions by LepteridineTM which impair gelatinase activity, possibly through perturbed tethering of MMP-9 to the gelatin matrix. Molecular modelling analyses were equivocal over interactions at the S1′ pocket versus the fibronectin II domain, while molecular dynamic calculations indicated rapid exchange kinetics. No significant degradation of synthetic or natural LepteridineTM in Mānuka honey occurred during simulated gastrointestinal digestion. MMP-9 regulates skin and gastrointestinal inflammatory responses and extracellular matrix remodelling. These results potentially implicate LepteridineTM bioactivity in Mānuka honey's reported beneficial effects on wound healing via topical application and anti-inflammatory actions in gastrointestinal disorder models via oral consumption. [ABSTRACT FROM AUTHOR]

Norovirus is the leading cause of viral gastroenteritis worldwide, and there are no approved vaccines or therapeutic treatments for chronic or severe norovirus infections. The structural characterisation of the norovirus protease and drug development has predominantly focused upon GI.1 noroviruses, despite most global outbreaks being caused by GII.4 noroviruses. Here, we determined the crystal structures of the GII.4 Sydney 2012 ligand-free norovirus protease at 2.79 Å and at 1.83 Å with a covalently bound high-affinity (IC50 = 0.37 µM) protease inhibitor (NV-004). We show that the active sites of the ligand-free protease structure are present in both open and closed conformations, as determined by their Arg112 side chain orientation. A comparative analysis of the ligand-free and ligand-bound protease structures reveals significant structural differences in the active site cleft and substrate-binding pockets when an inhibitor is covalently bound. We also report a second molecule of NV-004 non-covalently bound within the S4 substrate binding pocket via hydrophobic contacts and a water-mediated hydrogen bond. These new insights can guide structure-aided drug design against the GII.4 genogroup of noroviruses. [ABSTRACT FROM AUTHOR]

Anticoagulant compounds are likely to play an important role in the control of commensal rodents for crop protection and conservation for the foreseeable future. However, there are concerns regarding their persistence and the development of more widespread resistance. We are seeking to retrieve and retain older alternatives as well as developing novel rodenticides. Our three-pronged approach is, firstly, to improve the performance of older non-anticoagulant rodenticides, such as sodium fluoroacetate (1080) and zinc phosphide; secondly to optimise the performance of 1st-generation anticoagulants; and thirdly, to identify alternatives to anticoagulant rodenticides with the same mode of action as para-aminopropiophenone (PAPP), which was registered in New Zealand as a predacide in April 2011. Zinc phosphide was also registered in New Zealand for the first time in 2011, and combinations of ultra-low-dose cholecalciferol with first generation anticoagulants are being advanced to provide the performance characteristics of a 2nd-generation anticoagulant with a lower risk of bioaccumulation and secondary poisoning.

There is a need in New Zealand for a new, more advanced generation of toxins to minimize the impact of invasive animals. A new pest control agent, para-aminopropiophenone (PAPP), represents a lead candidate presently undergoing registration for the humane control of stoats and feral cats. It exhibits low toxicity to most bird species, no secondary poisoning risk, and has a simple and highly effective antidote. PAPP induces methemoglobinemia (MtHb), which acts to prevent oxygen from binding to red blood cells. This reduces oxygen supply to the brain, causing animals to become lethargic, sleepy, and unconscious prior to eventual death in 1 to 2 hours. Despite such promise, to date no previous study has comprehensively examined the effect of modifying the structure of PAPP on MtHb induction. Using PAPP as a platform, this paper describes the design, synthesis, and bioevaluation of PAPP-like red blood cell toxins. The impacts of introducing groups of varying electronic nature at different positions on the PAPP molecule are presently being evaluated. Analogues are synthesized and their MtHb-inducing properties determined using an in vitro assay to establish a formal structure-activity profile. In vivo evaluation in rats is used to assess both their acute toxicity and humaneness of potential candidates. Structure-activity profiles are discussed with the objective of optimizing the bioavailability and potency of PAPP-like compounds to target, high priority pests, particularly rodents.

In New Zealand, sodium fluoroacetate (1080) has been used for vertebrate pest control for several decades. Since the 1990s, some 1080 users have switched to brodifacoum for possum and rodent control because of its ready availability and ease of use. An awareness that field use of brodifacoum results in persistent residues provides the impetus to develop alternatives and provide new tools and greater flexibility. Looking to the future, we seek toxins which increasingly combine “low-residue” characteristics with humaneness, and more selective bait and delivery systems enabling better and more acceptable control of possums, wallabies, mustelids, rodents, feral cats, and rabbits. Experience gained in the 1990s with the introduction of cholecalciferol (Feracol®) and a cyanide pellet (Feratox®), which both kill possums without secondary poisoning, underpins the extension in 2009 of the Feratox® registration to include introduced Dama wallabies. To date, zinc phosphide has not been registered in NZ, despite its field use in Australia and the U.S. and low secondary poisoning risk compared with 1080. Research and registration dossiers are being assessed in 2009-10 for zinc phosphide containing products for possum and rodent control. Registration documents are also being prepared for a combination of cholecalciferol and coumatetralyl to provide a slow-acting alternative to brodifacoum for the field control of possums, rodents, and rabbits with low risk of bio-accumulation. Anticipated timelines for product availability are 2010 (zinc phosphide) and 2011-13 (cholecalciferol and coumatetralyl). Our intention now is to move beyond these conventional rodenticides and develop new vertebrate pesticides. For example, we are pursuing the registration of para-aminopropiophenone (PAPP) for humane control of stoats and feral cats, and a series of related novel toxins and other compounds that target the red blood cell for other pest species including rodents. PAPP products should be available in 2010, subject to registration approvals. New research initiatives in 2010 will increasingly result in a shift in focus to the development of novel rodenticides aided by new international research collaborations.