Chitin metabolism: a target for drugs against parasites

Spindler, Klaus-Dieter; Spindler-Barth, Margarethe; Londershausen, Michael

doi:10.1007/bf00928180

Cited by 70 publications

(42 citation statements)

References 38 publications

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“…Because chitinases are widely expressed in insects, plants, nematodes, fungi, and bacteria (13), and human chitinases with unknown function have been discovered (14), it was important to first determine the specificity of closantel for OvCHT1. Closantel was evaluated against chitinases from Brugia malayi, a related filarial nematode, and Entamoeba histolytica and, Plasmodium falciparum, protozoans, in addition to the human chitotriosidase.…”

Section: Discussionmentioning

confidence: 99%

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Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Gloeckner

Garner

Mersha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm’s metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel’s effects, a retro-fragment-based study was used to define structural elements critical for closantel’s chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.

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Section: Discussionmentioning

confidence: 99%

“…While knowledge of chitin biosynthesis in nematodes is limited (13), two classes of enzymes are critical for maintenance of the pathway, chitin synthases and chitinases. The dynamic synthesis and degradation of chitin by these enzymes is a prerequisite for organism development and, thus, serves as a target for growth control.…”

mentioning

confidence: 99%

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Gloeckner

Garner

Mersha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In plants, chitinases/lysozymes themselves likely form part of innate immune system important for host defense against invading pathogenic bacteria and fungi (31). Insect or nematode chitinases are likely essential to certain life cycle events such as molting of the larval exoskeleton or casting of the egg shell (32). Similarly, protozoans increase chitin synthesis (33) and chitinase activity (34) during encystation.…”

Section: Discussionmentioning

confidence: 99%

“…As for the carbohydrate recognition of ECF, human ecalectin that binds to carbohydrates (␤-galactosides) possesses ECF activity (30). The ability to recognize carbohydrate may be another aspect of ECF-L in the protective immunity against parasitic infections because chitin-related carbohydrates are an important component of the exoskeleton of larvae and egg shells in nematodes (32).…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Novel Eosinophil Chemotactic Cytokine (ECF-L) as a Chitinase Family Protein

Owhashi

Arita

Hayai

2000

Journal of Biological Chemistry

121

129

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A novel eosinophil chemotactic cytokine (ECF-L) was purified from the culture supernatant of splenocytes of mice by a combination of anion-exchange chromatography, Procion red-agarose affinity chromatography, size exclusion high performance liquid chromatography (HPLC), and reverse phase HPLC. The NH 2 -terminal amino acid sequence was determined by direct protein sequencing. An ECF-L cDNA clone of 1,506 nucleotides was isolated from a cDNA library, and the nucleotide sequence predicted a mature protein of 397 amino acids. A recombinant ECF-L showed a level of eosinophil chemotactic activity comparable with that of natural ECF-L, and the activity was inhibited by a monoclonal antibody to ECF-L. ECF-L also attracted T lymphocytes and bone marrow polymorphonuclear leukocytes in vitro, whereas it caused selective extravasation of eosinophils in vivo. ECF-L mRNA was highly expressed in spleen, bone marrow, lung, and heart. A comprehensive GenBank data base search revealed that ECF-L is a chitinase family protein. ECF-L retains those amino acids highly conserved among chitinase family proteins, but Asp and Glu residues essential for the proton donation in hydrolysis were replaced by Asn and Gln, respectively. Although ECF-L contains a consensus CXC sequence near the NH 2 terminus akin to chemokine family proteins, the rest of ECF-L shows poor homology with chemokines.

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Review: Approaches to New Parasiticides

Londershausen

1996

Pestic. Sci.

140

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Intensive use of parasiticides has sometimes led to severe resistance in arthropods and helminths of veterinary importance. In the context of the growing awareness of parasitic diseases, this has created a public demand for effective and safe control agents. During the last two decades considerable knowledge in parasite neurophysiology and endocrinology has accumulated which allows the development of new screening procedures and target‐site‐directed approaches for the discovery of new drugs. The suitability of this strategic approach is discussed on the basis of recent discoveries of new chemical and natural compounds. In particular, target sites such as GABAA receptors, muscarinic and nicotinic acetylcholine receptors, cuticle synthesis and degradation, ecdysteroid receptors, the calcium release channel and semiochemicals have been selected in order to demonstrate the current approaches to identify new chemical entities, biologically active against nematodes and arthropods.

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Chitin metabolism: a target for drugs against parasites

Cited by 70 publications

References 38 publications

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Identification of a Novel Eosinophil Chemotactic Cytokine (ECF-L) as a Chitinase Family Protein

Review: Approaches to New Parasiticides

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