Opinion
Unravelling the moulting degradome: new opportunities for chemotherapy?

https://doi.org/10.1016/j.pt.2007.04.003Get rights and content

Replacement of the nematode cuticle with a newly synthesized cuticle (a process known as moulting) occurs four times during larval development. Therefore, the key components of this essential developmental process represent attractive targets for new chemotherapeutic strategies. Recent advances in understanding the molecular genetics of nematode moulting should stimulate and facilitate development of novel drugs that target the essential molecules of the moulting cycle. In particular, we argue that further understanding of the moulting degradome and its key peptidase members offers an important opportunity for the development of novel antinematode agents.

Section snippets

Targeting the moult

The ecdysozoa (see Glossary) surround their bodies with a cuticle that supports body shape, provides a protective barrier against the external environment and functions as an exoskeleton for the anchorage of locomotory muscle. The rapid growth of the juvenile stages of ecdysozoa means that the exoskeleton can be quickly outgrown; therefore, these animals must periodically synthesize and lay down a new larger cuticle to enable the old confining cuticle to be shed. This moulting cycle is a

Recent advances in understanding nematode moulting

The nematode cuticle is a complex, three-layered structure that is composed predominantly of collagen [3]. During each larval stage, the nematode enters a period of inactivity, known as lethargus, when the old cuticle begins to disconnect from the underlying hypodermis. Apolysis of the old cuticle subsequently occurs and this enables the newly synthesized cuticle to be secreted into the space that has been created. After movement to loosen the old cuticle, ecdysis occurs 4, 5.

Several important

Peptidases as attractive targets for disease control

Undoubtedly one of the major challenges is the development of biocides that are active against parasitic nematodes but which are relatively nontoxic to the host. Encouragingly, there are several excellent examples of the development of highly selective peptidase inhibitors [9]. For example, aspartic-peptidase inhibitors are used in the treatment of HIV infection [10]. Interestingly, there is evidence that aspartic peptidases of several opportunistic parasites that infect HIV patients might be

Concluding remarks

Given the ancestral roots of moulting, many targets are likely to be well conserved among nematodes and, hence, provide good opportunities for the development of new antinematode agents. Successful replacement of the nematode cuticle is dependent upon being able to lay down new cuticle while at the same time detaching the old cuticle. The secretion of peptidases within the moult cycle to elicit detachment is seen as a key event while, at the same time, newly synthesized cuticle must be

Acknowledgements

We acknowledge Clare Nicol and Adrian Hick for their electron microscopy work and the Biotechnology and Biological Sciences Research Council for funding (BBS/B/11192).

Glossary

Apolysis
the separation of the cuticle from the epidermis in members of the ecdysozoa.
Collagen
long fibrous structural protein composed predominantly of glycine-X-Y triplet amino acid repeats.
Degradome
the complete repertoire of peptidases in an organism or the subset of peptidases that is involved in a defined biological event.
Ecdysozoa
group of animals that possess a cuticle that is periodically shed during development, includes arthropods and nematodes.
Ecdysis
periodic shedding of the exoskeleton

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