Metal complexes and metalloproteases: targeting conformational diseases
Giuseppe Grasso1, Sylvestre Bonnet
1Chemistry Department, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania, Italy. grassog@unict.it.
Abstract:
In recent years many metalloproteases (MPs) have been shown to play important roles in the development of various pathological conditions. Although most of the literature is focused on matrix MPs (MMPs), many other MPs have been demonstrated to be involved in the degradation of peptides or proteins whose accumulation and dyshomeostasis are considered as being responsible for the development of conformational diseases, i.e., diseases where non-native protein conformations lead to protein aggregation. It seems clear that, at least in principle, it must be possible to control the levels of many aggregation-prone proteins not only by reducing their production, but also by enhancing their catabolism. Metal complexes that can perform this function were designed and tested according to at least two different strategies: (i) intervening on the endogenous MPs by directly or indirectly modulating their activity; (ii) acting as artificial MPs, replacing or synergistically functioning with endogenous MPs. These two different bioinorganic approaches are widely represented in the current literature and the aim of this review is to rationally organize and discuss both of them so as to give a critical insight into these approaches and highlighting their limitations and future perspectives.
Insights
Metalloproteases (MPs) are crucial in diseases. This review explores metal complexes as artificial MPs to control protein aggregation in conformational diseases by enhancing protein catabolism.
Area of Science:
- Bioinorganic Chemistry
- Biochemistry
- Pathology
Background:
- Metalloproteases (MPs) play significant roles in pathological conditions.
- While matrix MPs (MMPs) are widely studied, other MPs are involved in degrading proteins implicated in conformational diseases.
- Protein aggregation due to dyshomeostasis of non-native protein conformations causes conformational diseases.
Purpose of the Study:
- To organize and critically discuss bioinorganic approaches for controlling protein aggregation.
- To provide insight into the limitations and future perspectives of these strategies.
- To explore the use of metal complexes as therapeutic agents for conformational diseases.
Main Methods:
- Reviewing literature on metalloprotease-modulating metal complexes.
- Analyzing strategies involving direct/indirect modulation of endogenous MPs.
- Examining approaches using metal complexes as artificial MPs.
Main Results:
- Two main bioinorganic strategies exist: modulating endogenous MPs and employing artificial MPs.
- Metal complexes offer potential for controlling aggregation-prone proteins by enhancing catabolism.
- Both strategies have limitations and require further investigation.
Conclusions:
- Metal complexes represent a promising therapeutic avenue for conformational diseases.
- Further research is needed to overcome limitations and optimize these bioinorganic strategies.
- Controlling protein catabolism via MPs is a viable approach for disease management.
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