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Article ; Online: Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

Buckingham, Steven D / Mann, Harry-Jack / Hearnden, Olivia K / Sattelle, David B

BioEssays : news and reviews in molecular, cellular and developmental biology

2020 Volume 42, Issue 9, Page(s) e2000011

Abstract: The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a ... ...

Abstract	The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re-engineered to serve as a new candidate therapeutic agent. The L-glutamate-gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L-glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L-glutamate-induced hyper-excitation and toxicity. Variant GluCls, with their inhibitory responses to L-glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L-glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.
MeSH term(s)	Drug Discovery ; Glutamic Acid ; Humans ; Neurons ; Pharmaceutical Preparations
Chemical Substances	Pharmaceutical Preparations ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2020-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202000011
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Article ; Online: Insect toxins - selective pharmacological tools and drug/chemical leads.

Kachel, Hamid S / Buckingham, Steven D / Sattelle, David B

Current opinion in insect science

2018 Volume 30, Page(s) 93–98

Abstract: Insect toxins comprise a diverse array of chemicals ranging from small molecules, polyamines and peptide toxins. Many target nervous system and neuromuscular ion channels and so rapidly affect the behaviour of animals to which the toxin is applied or ... ...

Abstract	Insect toxins comprise a diverse array of chemicals ranging from small molecules, polyamines and peptide toxins. Many target nervous system and neuromuscular ion channels and so rapidly affect the behaviour of animals to which the toxin is applied or injected. Other modes of action have also been identified. Wasps, bees, flies, beetles and ants generate a rich arsenal of channel-active toxins, some of which offer selective pharmacological probes that target particular ion channels, while others act on more than one type of channel. Philanthotoxins from the digger wasp have been fruitful in adding to our understanding of ligand-gated ion channels both in the nervous system and at neuromuscular junctions. Fire ants produce the toxic alkaloid solenopsin, a molecule which has stimulated attempts to generate synthetic compounds with insecticidal activity. Apamin from bee venom targets calcium-activated potassium channels, which can in turn influence the release of neuropeptides. Melittin, another bee venom component, is a membrane-acting peptide. The saliva of the assassin bug contains toxins that target the voltage-gated calcium channels of their insect prey. Certain beetles produce diamphotoxin, a haemolytic peptide toxin with traditional use as an arrow poison and others generate leptinotarsin with similar properties. Mastoparan is a powerful peptide toxin present in the venom of wasps. Its toxic actions can be engineered out leaving a potent antimicrobial molecule of interest. In this short review we describe the actions of selected insect toxins and evaluate their potential as neuroactive pharmacological tools, candidate lead molecules for insect control and therapeutic candidates with potential antimicrobial, antiviral and anti-cancer applications.
MeSH term(s)	Animals ; Arthropod Venoms/chemistry ; Arthropod Venoms/pharmacology ; Insect Control/instrumentation ; Insecta/drug effects ; Toxins, Biological/chemistry ; Toxins, Biological/pharmacology
Chemical Substances	Arthropod Venoms ; Toxins, Biological
Language	English
Publishing date	2018-10-09
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2772833-X
ISSN	2214-5753 ; 2214-5745
ISSN (online)	2214-5753
ISSN	2214-5745
DOI	10.1016/j.cois.2018.10.001
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Article ; Online: Calcium signalling in mammalian cell lines expressing wild type and mutant human α1-Antitrypsin.

Malintan, Nancy T / Buckingham, Steven D / Lomas, David A / Sattelle, David B

Scientific reports

2019 Volume 9, Issue 1, Page(s) 17293

Abstract: A possible role for calcium signalling in the autosomal dominant form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), has been proposed, which may point towards a mechanism by which cells could sense and respond to the ... ...

Abstract	A possible role for calcium signalling in the autosomal dominant form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), has been proposed, which may point towards a mechanism by which cells could sense and respond to the accumulation of mutant serpin polymers in the endoplasmic reticulum (ER). We therefore explored possible defects in Ca
MeSH term(s)	Animals ; CHO Cells ; Calcium/metabolism ; Calcium Signaling/genetics ; Cricetulus ; Epilepsies, Myoclonic/genetics ; Epilepsies, Myoclonic/pathology ; Heredodegenerative Disorders, Nervous System/genetics ; Heredodegenerative Disorders, Nervous System/pathology ; Humans ; Microscopy, Confocal ; Mutation ; Optical Imaging ; alpha 1-Antitrypsin/genetics ; alpha 1-Antitrypsin/metabolism
Chemical Substances	SERPINA1 protein, human ; alpha 1-Antitrypsin ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-11-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-53535-1
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Article: Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

Buckingham, Steven D / Mann, Harry‐Jack / Hearnden, Olivia K / Sattelle, David B

BioEssays. 2020 Sept., v. 42, no. 9

2020

Abstract	The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.
Keywords	chlorides ; drugs ; epilepsy ; genome ; glutamic acid ; humans ; neurons ; therapeutics ; toxicity
Language	English
Dates of publication	2020-09
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202000011
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Article ; Online: Cost-Effectiveness of Closed-Loop Automated Insulin Delivery Using the Cambridge Hybrid Algorithm in Children and Adolescents with Type 1 Diabetes: Results from a Multicenter 6-Month Randomized Trial.

Journal of diabetes science and technology

2024 , Page(s) 19322968241231950

Abstract: Background/objective: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 ... ...

Abstract	Background/objective: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 diabetes (T1D). Methods: This multicenter, binational, parallel-controlled trial randomized 133 insulin pump using participants aged 6 to 18 years to either AID (n = 65) or usual care (n = 68) for 6 months. Both within-trial and lifetime cost-effectiveness were analyzed. Analysis focused on the treatment subgroup (n = 21) who received the much more reliable CamAPS FX hardware iteration and their contemporaneous control group (n = 24). Lifetime complications and costs were simulated via an updated Sheffield T1D policy model. Results: Within-trial, both groups had indistinguishable and statistically unchanged health-related quality of life, and statistically similar hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis (DKA) event rates. Total health care utilization was higher in the treatment group. Both the overall treatment group and CamAPS FX subgroup exhibited improved HbA Conclusions: For children and adolescents with T1D on insulin pump therapy, AID using the Cambridge algorithm appears cost-effective below a £20 000/QALY threshold (United Kingdom) and cost saving (United States).
Language	English
Publishing date	2024-03-17
Publishing country	United States
Document type	Journal Article
ISSN	1932-2968
ISSN (online)	1932-2968
DOI	10.1177/19322968241231950
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Article ; Online: Automated phenotyping of mosquito larvae enables high-throughput screening for novel larvicides and offers potential for smartphone-based detection of larval insecticide resistance.

Buckingham, Steven D / Partridge, Frederick A / Poulton, Beth C / Miller, Benjamin S / McKendry, Rachel A / Lycett, Gareth J / Sattelle, David B

PLoS neglected tropical diseases

2021 Volume 15, Issue 6, Page(s) e0008639

Abstract: Pyrethroid-impregnated nets have contributed significantly to halving the burden of malaria but resistance threatens their future efficacy and the pipeline of new insecticides is short. Here we report that an invertebrate automated phenotyping platform ( ... ...

Abstract	Pyrethroid-impregnated nets have contributed significantly to halving the burden of malaria but resistance threatens their future efficacy and the pipeline of new insecticides is short. Here we report that an invertebrate automated phenotyping platform (INVAPP), combined with the algorithm Paragon, provides a robust system for measuring larval motility in Anopheles gambiae (and An. coluzzi) as well as Aedes aegypti with the capacity for high-throughput screening for new larvicides. By this means, we reliably quantified both time- and concentration-dependent actions of chemical insecticides faster than using the WHO standard larval assay. We illustrate the effectiveness of the system using an established larvicide (temephos) and demonstrate its capacity for library-scale chemical screening using the Medicines for Malaria Venture (MMV) Pathogen Box library. As a proof-of-principle, this library screen identified a compound, subsequently confirmed to be tolfenpyrad, as an effective larvicide. We have also used the INVAPP / Paragon system to compare responses in larvae derived from WHO classified deltamethrin resistant and sensitive mosquitoes. We show how this approach to monitoring larval response to insecticides can be adapted for use with a smartphone camera application and therefore has potential for further development as a simple portable field-assay with associated real-time, geo-located information to identify hotspots.
MeSH term(s)	Aedes/drug effects ; Animals ; Anopheles/drug effects ; Automation ; Culicidae/classification ; Culicidae/drug effects ; High-Throughput Screening Assays ; Insecticide Resistance ; Insecticides/pharmacology ; Larva/classification ; Larva/drug effects ; Mosquito Control ; Motor Activity/drug effects ; Phenotype ; Pyrethrins/pharmacology ; Smartphone ; Temefos/pharmacology
Chemical Substances	Insecticides ; Pyrethrins ; Temefos (ONP3ME32DL)
Language	English
Publishing date	2021-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0008639
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Article: Functional genomics: applying calcium imaging and RNA interference to Drosophila cell lines to identify new roles for gene products.

Buckingham, Steven D

Invertebrate neuroscience : IN

2006 Volume 6, Issue 3, Page(s) 141–144

Abstract: The selective knockdown of genes using RNA interference, and the analysis of the resultant phenotype using calcium imaging, is proving to be a powerful combination for discovering new genes involved in calcium signalling. This technical note describes ... ...

Abstract	The selective knockdown of genes using RNA interference, and the analysis of the resultant phenotype using calcium imaging, is proving to be a powerful combination for discovering new genes involved in calcium signalling. This technical note describes the application of this approach to the Drosophila S2 cell line and its derivatives.
MeSH term(s)	Animals ; Calcium/metabolism ; Cell Line ; Diagnostic Imaging ; Drosophila/genetics ; Genomics/methods ; Macrophages/metabolism ; RNA Interference
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2006-08-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2003354-0
ISSN	1439-1104 ; 1354-2516
ISSN (online)	1439-1104
ISSN	1354-2516
DOI	10.1007/s10158-006-0025-z
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Article ; Online: Modes of Action, Resistance and Toxicity of Insecticides Targeting Nicotinic Acetylcholine Receptors.

Ihara, Makoto / Buckingham, Steven D / Matsuda, Kazuhiko / Sattelle, David B

Current medicinal chemistry

2017 Volume 24, Issue 27, Page(s) 2925–2934

Abstract: Background: Nicotinic acetylcholine receptors (nAChRs) of insects play a key role in fast excitatory neurotransmission. Several classes of insecticides target insect nAChRs, which are composed of subunit members of a family of multiple subunit encoding ... ...

Abstract	Background: Nicotinic acetylcholine receptors (nAChRs) of insects play a key role in fast excitatory neurotransmission. Several classes of insecticides target insect nAChRs, which are composed of subunit members of a family of multiple subunit encoding genes. Alternative splicing and RNA A-to-I editing can add further to receptor diversity. Native and recombinant receptors have been explored as sites of insecticide action using radioligands, electrophysiology and site-directed mutagenesis. Methods: We have reviewed the properties of native and recombinant insect nAChRs, the challenges of functional recombinant insect nAChR expression, nAChR interactions with ligands acting at orthosteric and allosteric sites and in particular their interactions with insecticides. Results: Actions on insect nAChRs of cartap, neonicotinoids, spinosyns, sulfoxamines, butenolides and mesoionic insecticides are reviewed and current knowledge of their modes of action are addressed. Mutations that add to our understanding of insecticide action and those leading to resistance are discussed. Co-crystallisation of neonicotinoids with the acetylcholine binding protein (AChBP), a surrogate for the nAChR ligand binding domain, has proved instructive. Toxicity issues relating to insecticides targeting nAChRs are also considered. Conclusion: An overview of insecticide classes targeting insect nAChRs has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native nAChRs remains poorly understood and functional expression still presents difficulties. These topics together with improved understanding of the precise sites of insecticide actions on insect nAChRs will be the subject of future research.
MeSH term(s)	Animals ; Drug Resistance/drug effects ; Humans ; Insecticides/chemistry ; Insecticides/metabolism ; Insecticides/toxicity ; Macrolides/chemistry ; Macrolides/metabolism ; Macrolides/toxicity ; Neurons/drug effects ; Neurons/metabolism ; Nicotine/chemistry ; Nicotine/metabolism ; Protein Binding ; Pyridines/chemistry ; Pyridines/metabolism ; Pyridines/toxicity ; Pyrimidinones/chemistry ; Pyrimidinones/metabolism ; Pyrimidinones/toxicity ; Receptors, Nicotinic/chemistry ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Thiocarbamates/chemistry ; Thiocarbamates/metabolism ; Thiocarbamates/toxicity
Chemical Substances	Insecticides ; Macrolides ; Pyridines ; Pyrimidinones ; Receptors, Nicotinic ; Recombinant Proteins ; Thiocarbamates ; spinosyn A ; triflumezopyrim ; Nicotine (6M3C89ZY6R) ; carbamothioic acid, S,S'-(2-(dimethylamino)-1,3-propanediyl) ester (Z45YUY784H)
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867324666170206142019
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Article ; Online: Mechanisms of Action, Resistance and Toxicity of Insecticides Targeting GABA Receptors.

Buckingham, Steven D / Ihara, Makoto / Sattelle, David B / Matsuda, Kazuhiko

Current medicinal chemistry

2017 Volume 24, Issue 27, Page(s) 2935–2945

Abstract: Background: γ-Aminobutyric acid (GABA) receptors play a central role in fast inhibitory neurotransmission in insects. Several classes of insecticides targeting insect GABA-gated chloride channels have been developed. The important resistant to dieldrin ... ...

Abstract	Background: γ-Aminobutyric acid (GABA) receptors play a central role in fast inhibitory neurotransmission in insects. Several classes of insecticides targeting insect GABA-gated chloride channels have been developed. The important resistant to dieldrin GABA receptor subunit (RDL) has been used to investigate insecticide sites of action using radioligands, electrophysiology and site-directed mutagenesis. Although this important subunit readily forms robust functional homomeric receptors when expressed, alternative splicing and RNA A-to-I editing can generate diverse forms of the receptor. Methods: We have reviewed studies on native and recombinant insect GABA-gated chloride channels, their interactions with ligands acting at orthosteric and allosteric sites and their interactions with insecticides. Since some GABA receptor modulators act on L-glutamate-gated chloride channels, some comparisons are included. Results: The actions on GABA-gated chloride channels of polychlorocycloalkanes, cyclodienes, macrocyclic lactones, phenylpyrazoles, isoxazolines, and metadiamides are described and the mechanisms of action of members of these insecticide classes are addressed. Mutations that lead to resistance are discussed as they can be important in developing field diagnostic tests. Toxicity issues relating to insecticides targeting GABA-gated chloride channels are also addressed. An overview of all major insecticide classes targeting insect GABA-gated chloride channels has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native GABA receptors remains unknown and studies to clarify this are needed. Also, the precise sites of action of the recently introduced isoxazolines and meta-diamides will be of interest to pursue.
MeSH term(s)	Animals ; Drug Resistance/drug effects ; GABA Antagonists/chemistry ; GABA Antagonists/metabolism ; GABA Antagonists/toxicity ; Humans ; Insecta/drug effects ; Insecticides/chemistry ; Insecticides/metabolism ; Insecticides/toxicity ; Oxazoles/chemistry ; Oxazoles/metabolism ; Oxazoles/toxicity ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrazoles/toxicity ; Receptors, GABA/chemistry ; Receptors, GABA/genetics ; Receptors, GABA/metabolism ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry
Chemical Substances	GABA Antagonists ; Insecticides ; Oxazoles ; Pyrazoles ; Receptors, GABA ; Recombinant Proteins
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867324666170613075736
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Article: Data mining for protein-protein interactions in invertebrate model organisms.

Buckingham, Steven D

Invertebrate neuroscience : IN

2005 Volume 5, Issue 3-4, Page(s) 183–187

Abstract: Well-annotated genome databases are available for many invertebrate species, notably the fruitfly, Drosophila melanogaster, and the nematode, Caenorhabditis elegans. An adequate interpretation of this information at the biological level requires the ... ...

Abstract	Well-annotated genome databases are available for many invertebrate species, notably the fruitfly, Drosophila melanogaster, and the nematode, Caenorhabditis elegans. An adequate interpretation of this information at the biological level requires the exploration of the interactions between the gene products. Knowledge of protein interactions and the components of cell signalling pathways in the fly and worm are particularly valuable as hypotheses can be rapidly tested using the powerful genetic toolkits available. Invertebrates offer additional experimental advantages when attempting to characterise protein-protein interactions (PPIs). Their relatively small genome size compared to mammals helps to reduce missed interactions due to redundancy, and their function can be addressed using forward (mutants) and reverse (RNA interference) genetics. However, the researcher looking for evidence of PPIs for a protein of interest is faced with the challenge of extracting interaction data from sources that are highly varied, such as the results of microarray experiments in the unstructured text of research papers. This challenge is greatly reduced by a range of public databases of curated information, as well as publicly available, enhanced search engines, which can provide either direct experimental evidence for a PPI, or valuable clues for generating new hypotheses.
MeSH term(s)	Animals ; Databases, Protein ; Information Storage and Retrieval/methods ; Invertebrates/physiology ; Protein Interaction Mapping ; Proteins/metabolism ; Proteomics
Chemical Substances	Proteins
Language	English
Publishing date	2005-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2003354-0
ISSN	1439-1104 ; 1354-2516
ISSN (online)	1439-1104
ISSN	1354-2516
DOI	10.1007/s10158-005-0009-4
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