Current Topics in Medicinal Chemistry - Volume 16, Issue 27, 2016

Human serum albumin (HSA) is the major protein in blood plasma and is responsible for circulatory transport of a range of small molecules including fatty acids, metal ions and drugs. We previously identified the major plasma Zn2+ transport site on HSA and revealed that fatty-acid binding (at a distinct site called the FA2 site) and Zn2+ binding are interdependent via an allosteric mechanism. Since binding affinities of long-chain fatty acids exceed those of plasma Zn2+, this means that under certain circumstances the binding of fatty acid molecules to HSA is likely to diminish HSA Zn2+-binding, and hence affects the control of circulatory and cellular Zn2+ dynamics. This relationship between circulatory fatty acid and Zn2+ dynamics is likely to have important physiological and pathological implications, especially since it has been recognised that Zn2+ acts as a signalling agent in many cell types. Fatty acid levels in the blood are dynamic, but most importantly, chronic elevation of plasma fatty acid levels is associated with some metabolic disorders and disease states – including myocardial infarction and other cardiovascular diseases. In this article, we briefly review the metal-binding properties of albumin and highlight the importance of their interplay with fatty acid binding. We also consider the impact of this dynamic link upon levels and speciation of plasma Zn2+, its effect upon cellular Zn2+ homeostasis and its relevance to cardiovascular and circulatory processes in health and disease.

Among the human copper-containing monooxygenases, Tyrosinase (Ty) is an important enzyme involved in the determinant step of the biosynthetic pathway of melanin pigment. In this pathway, Ty catalyzes the tyrosine monooxygenation into L-DOPA-quinone, which is the precursor of the skin pigment melanin. Ty inhibitors/activators are a well-established approach for controlling in vivo melanin production, so their development has a huge economical and industrial impact. Moreover, recent publications highlight that targeting tyrosinase with inhibitors/activators to treat melanogenesis disorders is one of many possible approaches, due to the complex biochemical reaction involved in the melanin synthesis.

Malaria is one of the world’s most devastating diseases, particularly in the tropics. In humans, Plasmodium falciparum lives mainly within red blood cells, and malaria pathogenesis depends on the red blood cells being infected with the parasite. Nonesterified fatty acids (NEFAs), including cis-9-octadecenoic acid, and phospholipids have been critical for complete parasite growth in serum-free culture, although the efficacy of NEFAs in sustaining the growth of P. falciparum has varied markedly. Hexadecanoic acid and trans-9-octadecenoic acid have arrested development of the parasite, in association with down-regulation of genes encoding copper-binding proteins. Selective removal of Cu+ ions has blockaded completely the ring–trophozoite–schizont progression of the parasite. The importance of copper homeostasis for the developmental progression of P. falciparum has been confirmed by inhibition of copper-binding proteins that regulate copper physiology and function by associating with copper ions. These data have provided strong evidence for a link between healthy copper homeostasis and successive developmental progression of P. falciparum. Perturbation of copper homeostasis may be, thus, instrumental in drug and vaccine development for the malaria medication. We review the importance of copper homeostasis in the asexual growth of P. falciparum in relation to NEFAs, copperbinding proteins, apoptosis, mitochondria, and gene expression.

Pathological aggregation of endogenous proteins is a common feature of many neurodegenerative diseases. This is generally accompanied by elevated levels of oxidative stress associated with transition metal dyshomeostasis. As such, strategies targeted toward rectifying metal imbalance are increasingly becoming an attractive therapeutic option. One class of compound showing such therapeutic potential are the bis(thiosemicarbazone) metal complexes. These are small, orally bioavailable compounds capable of crossing the blood brain barrier and capable of delivering bioavailable metal intracellularly. Members of this family of compounds have been shown to successfully treat animal models of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Here we review the current evidence for the efficacy of bis(thiosemicarbazone) metal complexes in treating these diseases and discuss the implications for future development of these compounds.

Noble metal nanomaterials, such as gold or silver nanoparticles, exhibit unique photonic, electronic, catalytic and therapeutic properties. The high versatility in their synthesis, especially size and shape features, as well as in the surface functionalization by, e.g., physisorption, direct chemisorption of thiol derivatives and covalent binding through bifunctional linkers or specific affinity interactions, prompted their widespread and rising use as multifunctional platforms for theranostic purposes. In this paper, the recent developments of gold and silver nanoparticles for application in biosensing, medical imaging, diagnosis and therapy is reviewed from the following five aspects: (1) the gold and silver nanomaterials intrinsic properties of biomedical interest; (2) the synthesis of noble metal nanoparticles by chemical, physical and biological/green processes; (3) the applications of gold and silver nanoparticles in imaging, diagnostic and therapeutic mode; (4) the surface functionalization processes for targeting, controlled drug loading and release, triggered pathways of cellular uptake and tissue distribution; and (5) nanotoxicity. The historical developments and the most recent applications have been focused on, together with suggested strategies for future more efficacious, targeted delivery.

The description of the cell life needs not only the knowledge of its genome and proteome, but also of the location of the metal ions and their different complex species in the subcellular compartments, that is of metallome. The cross-talk among these players of the omics’ world secures the cellular homeostasis by means of a complex network, the alteration of which may give rise to many diseases. Copper and zinc ions levels regulate protein expression and metal-responsive transcription factors and in many pathologies metal dyshomeostasis induces to aberrant expression of different factors. microRNAs, a class of a small non-coding RNA molecules, act as RNA silencing and post-transcriptional regulators of gene expression contributing also to metal regulatory activity. The aim of the present review is to present how metals dyshomeostasis can be cause of diseases, involving different and specific metal chaperones, metal transporters, metalloproteins, small molecules and metal-sensing transcription factors. Two distinct classes of pathologies, cancer and osteoarthritis, are discussed starting from the metallostasis (metal homeostasis) and turning up to miRNAs regulation. The understanding of post-translational regulation, driven by metal ions sensing, may help to identify more specific targets and drugs to pathologies in which metal ions are involved.