Metal complexes and metalloproteases: targeting conformational diseases

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.

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

“…Moreover, huge number of recent publications support that metal ions also play a crucial role in neurodegeneration . The interactions of metal ions with prion protein and its peptide fragments and with amyloid‐β peptide have been extensively studied and the most important results are summarized in several reviews . On the contrary, the association of metal ions with tau protein and its various peptide fragments are much less studied and the results are partly contradictory.…”

Mass spectrometry is a multifaceted weapon to be used in the battle against Alzheimer's disease: Amyloid beta peptides and beyond

“…After limits of the “amyloid hypothesis” of AD were found, the “metal hypothesis” was formulated to take into account the experimental evidence that showed the presence of metal ions (mainly copper and zinc) in the amyloid plaques and their involvement in many processes linked to AD . For this reason, MS investigations have been applied to quantify metal ions in a biological specimen to find any significantly statistically differences between AD patients and controls.…”

“…In other words, the dyshomeostasis of Aβ could be just a consequence of another altered feature among those mentioned above, which, although not directly detectable, could be the main causative agent of the disease. Taking into account that Aβ peptides have been recognized to have important physiological roles and that is only accumulation of the peptides that becomes pathological, catabolism of Aβ rather than its production assumes a pivotal role in the etiology of the disease and possible therapeutic strategies could therefore target Aβ degradation; for example an increasing Aβ proteolytic enzyme's activity …”

Synthesis, X-ray crystal structure and biological evaluation of zinc(II)-dichlorido complexes with 9-deazahypoxathine derivatives

“…Therefore, the possibility of positively and/or negatively modulating the activity of MMPs represents an interesting therapeutic approach in the treatment of some conformational, prion or neoplastic diseases. Subsequently, a great number of organic compounds showing MMP-modulating activity, as well as a wide spectrum of metal-based complexes acting as inhibitors or activators of MMP activity, were previously reported [10]. For example, zinc(II)-based complexes involving derivatives of kinetin demonstrated MMP-2 activation properties [11].…”