Enzymology of the nematode cuticle: A potential drug target?

Page, Antony P.; Stepek, Gillian; Winter, Alan D.; Pertab, David

doi:10.1016/j.ijpddr.2014.05.003

Cited by 102 publications

(91 citation statements)

References 95 publications

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“…The cuticle is first synthesized during late embryogenesis (Page et al., 2014). In the current study, 26 DEGs were annotated as cuticle components (Table S1).…”

Section: Discussionmentioning

confidence: 99%

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

O’Neill

Ballesteros

Tritten

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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The use of microfilaricidal drugs for the control of onchocerciasis and lymphatic filariasis (LF) necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by the availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate. FLBZ has demonstrated potent macrofilaricidal effects in a number of experimental rodent models and in one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration campaigns due to its limited oral bioavailability. A new formulation that enables sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. Identification of drug-derived effects is important in ascertaining a dosage regimen which is predicted to be lethal to the parasite in situ. In previous histological studies, exposure to FLBZ induced damage to tissues required for reproduction and survival at pharmacologically relevant concentrations. However, more precise and quantitative indices of drug effects are needed. This study assessed drug effects using a transcriptomic approach to confirm effects observed histologically and to identify genes which were differentially expressed in treated adult female Brugia malayi. Comparative analysis across different concentrations (1 μM and 5 μM) and durations (48 and 120 h) provided an overview of the processes which are affected by FLBZ exposure. Genes with dysregulated expression were consistent with the reproductive effects observed via histology in our previous studies. This study revealed transcriptional changes in genes involved in embryo development. Additionally, significant downregulation was observed in genes encoding cuticle components, which may reflect changes in developing embryos, the adult worm cuticle or both. These data support the hypothesis that FLBZ acts predominantly on rapidly dividing cells, and provides a basis for selecting molecular markers of drug-induced damage which may be of use in predicting efficacious FLBZ regimens.

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“…The cuticle is first synthesized during late embryogenesis (Page et al., 2014). In the current study, 26 DEGs were annotated as cuticle components (Table S1).…”

Section: Discussionmentioning

confidence: 99%

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

O’Neill

Ballesteros

Tritten

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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“…Although the observable biomechanics and major morphological features of C. elegans molting were first described nearly 40 years ago (Hirsh et al 1976;Singh and Sulston 1978), the molecular and cellular mechanisms underlying this complex process are largely unknown. Notably, molting occurs in both pathogenic and nonpathogenic nematode species, and molting factors have been proposed as potential targets for antiparasitic drugs (Page et al 2014;Gooyit et al 2015).Mechanistically, molting is the process by which nematodes remodel their epidermal apical extracellular matrix (ECM), termed the cuticle. In C. elegans larvae and adults, the cuticle serves as a mechanical barrier and provides physical and chemical protection from the environment (Page and Johnstone 2007).…”

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confidence: 99%

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confidence: 99%

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Lažetić¹,

Fay

2017

Genetics

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Molting is an essential developmental process in nematodes during which the epidermal apical extracellular matrix, the cuticle, is remodeled to accommodate further growth. Using genetic approaches, we identified a requirement for three conserved ankyrin repeat-rich proteins, MLT-2/ANKS6, MLT-3/ANKS3, and MLT-4/INVS, in Caenorhabditis elegans molting. Loss of mlt function resulted in severe defects in the ability of larvae to shed old cuticle and led to developmental arrest. Genetic analyses demonstrated that MLT proteins functionally cooperate with the conserved NIMA kinase family members NEKL-2/NEK8 and NEKL-3/NEK6/NEK7 to promote cuticle shedding. MLT and NEKL proteins were specifically required within the hyp7 epidermal syncytium, and fluorescently tagged mlt and nekl alleles were expressed in puncta within this tissue. Expression studies further showed that NEKL-2-MLT-2-MLT-4 and NEKL-3-MLT-3 colocalize within largely distinct assemblies of apical foci. MLT-2 and MLT-4 were required for the normal accumulation of NEKL-2 at the hyp7-seam cell boundary, and loss of mlt-2 caused abnormal nuclear accumulation of NEKL-2. Correspondingly, MLT-3, which bound directly to NEKL-3, prevented NEKL-3 nuclear localization, supporting the model that MLT proteins may serve as molecular scaffolds for NEKL kinases. Our studies additionally showed that the NEKL-MLT network regulates early steps in clathrin-mediated endocytosis at the apical surface of hyp7, which may in part account for molting defects observed in nekl and mlt mutants. This study has thus identified a conserved NEKL-MLT protein network that regulates remodeling of the apical extracellular matrix and intracellular trafficking, functions that may be conserved across species.KEYWORDS C. elegans; molting; NIMA kinase; endocytosis; ankyrin repeat proteins M OLTING is a ubiquitous process in nematode species, including Caenorhabditis elegans, and is required for organismal growth and development. Although the observable biomechanics and major morphological features of C. elegans molting were first described nearly 40 years ago (Hirsh et al. 1976;Singh and Sulston 1978), the molecular and cellular mechanisms underlying this complex process are largely unknown. Notably, molting occurs in both pathogenic and nonpathogenic nematode species, and molting factors have been proposed as potential targets for antiparasitic drugs (Page et al. 2014;Gooyit et al. 2015).Mechanistically, molting is the process by which nematodes remodel their epidermal apical extracellular matrix (ECM), termed the cuticle. In C. elegans larvae and adults, the cuticle serves as a mechanical barrier and provides physical and chemical protection from the environment (Page and Johnstone 2007). In addition, similar to the chitin-based exoskeleton of insects and other arthropods, the cuticle is required to facilitate organismal movement in conjunction with attached underlying muscles. Unlike arthropods, however, in nematodes the cuticle is comprised primarily of collagens (Page and Johnstone 20...

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“…In nematodes, the cuticle is responsible for the primary interface with the environment as well as required for body shape and movement [53, 54]. Similar to mosquitoes, the epicuticle layer is composed of lipid-rich molecules as well as glycoproteins.…”

Section: Physiochemical Barriers In Drug Deliverymentioning

confidence: 99%

Nano-enabled delivery of diverse payloads across complex biological barriers

Ross

Brenza

Binnebose

et al. 2015

Journal of Controlled Release

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Complex biological barriers are major obstacles for preventing and treating disease. Nano-carriers are designed to overcome such obstacles by enhancing drug delivery through physiochemical barriers and improving therapeutic indices. This review critically examines both biological barriers and nano-carrier payloads for a variety of drug delivery applications. A spectrum of nano-carriers is discussed that have been successfully developed for improving tissue penetration for preventing or treating a range of infectious, inflammatory, and degenerative diseases.

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Enzymology of the nematode cuticle: A potential drug target?

Abstract: Graphical abstract

Cited by 102 publications

References 95 publications

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Nano-enabled delivery of diverse payloads across complex biological barriers

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