Developing drugs targeting transition metal homeostasis
Introduction
The proteome is composed of approximately 30% metalloproteins whose functions are dependent on the availability and delivery of transition metals. Disorders of transition metal homeostasis vary from genetic diseases of copper overload (Wilson’s disease) and deficiency (Menkes disease) to iron overload (hereditary haemochromatosis). Aberrant transition metal homeostasis is implicated in many other diseases, with intense interest in its role in cancer and neurodegenerative diseases.
In genetic diseases of metal overload there is an unambiguous link between transition metal status and disease symptoms. For decades, these diseases have been treated with chelators that bind the offending metals, leading to their excretion rather than accumulation in body tissues. Now, chelators and their metal-bound alter egos known as ionophores show promising activity in cancer and neurodegenerative diseases. The relationship between metal status and disease pathology and progression in other diseases is more complex. The inhibition of disease progression via altering metal homeostasis may result from: the elimination of excess metal, the redistribution of metals across cells and tissues or even the accumulation of metals to toxic levels in diseased tissue. To match these diverse objectives, the development of drugs targeting transition metal homeostasis now spans: (1) chelators and ionophores that bind and release metals; (2) inhibitors that target metal uptake and transport proteins; and (3) drugs that impact metal regulatory transcription factors. This review will cover recent developments in the design of drugs targeting iron, copper, zinc and manganese homeostasis in cancer and neurodegenerative diseases, with special emphasis on drugs that interfere with cellular metal trafficking (Figure 1).
Section snippets
Metal-binding chelators and metal-releasing ionophores
Chelators and ionophores target transition metal homeostasis at the molecular level by binding and releasing metals with the aim of eliminating excess metals, redistributing endogenous metals or depositing exogenous metals (Figure 2). Chelators have traditionally been used to treat heavy metal toxicity and diseases characterised by metal overload due to genetic defects that impair metal uptake or export pathways. While ionophores and chelators may be considered opposite to each other in that
Small molecule inhibitors of metal transport proteins
The development of drugs targeting metal transport proteins is dependent on an understanding of cellular metal transport pathways and their roles in disease pathogenesis. Our knowledge of the proteins involved in metal uptake, transport and export in humans is most detailed for copper [21], zinc [22] and iron [23], but even for these metals, much remains to be discovered.
In keeping with our limited understanding of metal transport in humans there are few drugs that directly target proteins
Targeting metal homeostasis through metal regulatory proteins
The ability of ferristatin II and other compounds to induce or inhibit the synthesis of hepcidin represents a third means of targeting metal homeostasis: through metal sensing and the regulation of metal homeostasis. Metal regulatory factors sense fluctuations in metal ion levels and, in response, alter gene expression via transcriptional, posttranscriptional and posttranslational mechanisms to maintain metal ion homeostasis [42]. Targeting these factors will enable the manipulation of
Conclusions and outlook
We have described three broad classes of drugs that target transition metal homeostasis: chelators and ionophores that remove, redistribute and deposit metals; small molecule inhibitors of proteins involved in metal transport and a nascent class of drugs that target metal regulatory proteins. A summary of their potential impacts on cellular metal homeostasis is shown in Figure 4.
As the best-developed class of drugs targeting metal homeostasis, chelators and ionophores are making their way into
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors acknowledge colleagues whose work was not cited due to space limitations. CMW is supported by a National Health and Medical Research Council (NHMRC) CJ Martin Fellowship. CH is an investigator of the Howard Hughes Medical Institute (HHMI) and is supported by National Institutes of Health GM071440.
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