Zn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein.

The spike protein (S) of SARS-CoV-2 is able to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor with a much higher affinity compared to other coronaviruses. The binding interface between the ACE2 receptor and the spike protein plays a critical role in the entry mechanism of the SARS-CoV-2 virus. There are specific amino acids involved in the interaction between the S protein and the ACE2 receptor. This specificity is critical for the virus to establish a systemic infection and cause COVID-19 disease. In the ACE2 receptor, the largest number of amino acids playing a crucial role in the mechanism of interaction and recognition with the S protein is located in the C-terminal part, which represents the main binding region between ACE2 and S. This fragment is abundant in coordination residues such as aspartates, glutamates, and histidine that could be targeted by metal ions. Zn2+ ions bind to the ACE2 receptor in its catalytic site and modulate its activity, but it could also contribute to the structural stability of the entire protein. The ability of the human ACE2 receptor to coordinate metal ions, such as Zn2+, in the same region where it binds to the S protein could have a crucial impact on the mechanism of recognition and interaction of ACE2-S, with consequences on their binding affinity that deserve to be investigated. To test this possibility, this study aims to characterize the coordination ability of Zn2+, and also Cu2+ for comparison, with selected peptide models of the ACE2 binding interface using spectroscopic and potentiometric techniques.

Biological Effects of Human Exposure to Environmental Cadmium.

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd2+ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure.

Thermodynamic Study of Oxidovanadium(IV) with Kojic Acid Derivatives: A Multi-Technique Approach.

The good chelating properties of hydroxypyrone (HPO) derivatives towards oxidovanadium(IV) cation, VIVO2+, constitute the precondition for the development of new insulin-mimetic and anticancer compounds. In the present work, we examined the VIVO2+ complex formation equilibria of two kojic acid (KA) derivatives, L4 and L9, structurally constituted by two kojic acid units linked in position 6 through methylene diamine and diethyl-ethylenediamine, respectively. These chemical systems have been characterized in solution by the combined use of various complementary techniques, as UV-vis spectrophotometry, potentiometry, NMR and EPR spectroscopy, ESI-MS spectrometry, and DFT calculations. The thermodynamic approach allowed proposing a chemical coordination model and the calculation of the complex formation constants. Both ligands L4 and L9 form 1:1 binuclear complexes at acidic and physiological pHs, with various protonation degrees in which two KA units coordinate each VIVO2+ ion. The joined use of different techniques allowed reaching a coherent vision of the complexation models of the two ligands toward oxidovanadium(IV) ion in aqueous solution. The high stability of the formed species and the binuclear structure may favor their biological action, and represent a good starting point toward the design of new pharmacologically active vanadium species.

Gold Clusters: From the Dispute on a Gold Chair to the Golden Future of Nanostructures.

The present work opens with an acknowledgement to the research activity performed by Luciana Naldini while affiliated at the Università degli Studi di Sassari (Italy), in particular towards gold complexes and clusters, as a tribute to her outstanding figure in a time and a society where being a woman in science was rather difficult, hoping her achievements could be of inspiration to young female chemists in pursuing their careers against the many hurdles they may encounter. Naldini's findings will be a key to introduce the most recent results in this field, showing how the chemistry of gold compounds has changed throughout the years, to reach levels of complexity and elegance that were once unimagined. The study of gold complexes and clusters with various phosphine ligands was Naldini's main field of research because of the potential application of these species in diverse research areas including electronics, catalysis, and medicine. As the conclusion of a vital period of study, here we report Naldini's last results on a hexanuclear cationic gold cluster, [(PPh3)6Au6(OH)2]2+, having a chair conformation, and on the assumption, supported by experimental data, that it comprises two hydroxyl groups. This contribution, within the fascinating field of inorganic chemistry, provides the intuition of how a simple electron counting may lead to predictable species of yet unknown molecular architectures and formulation, nowadays suggesting interesting opportunities to tune the electronic structures of similar and higher nuclearity species thanks to new spectroscopic and analytical approaches and software facilities. After several decades since Naldini's exceptional work, the chemistry of the gold cluster has reached a considerable degree of complexity, dealing with new, single-atom precise, materials possessing interesting physico-chemical properties, such as luminescence, chirality, or paramagnetic behavior. Here we will describe some of the most significant contributions.

Gold nanoparticles and cancer: Detection, diagnosis and therapy.

Gold nanoparticles (AuNPS) represent one of the most studied classes of nanomaterials for biomedical applications, especially in the field of cancer research. In fact, due to their unique properties and high versatility, they can be exploited under all aspects connected to cancer management, from early detection to diagnosis and treatment. AuNPs have thus been tested with amazing results as biosensors, contrast agents, therapeutics. Their importance as potent theranostics is undoubted, but the translation to clinical practice has been hampered by a series of aspects, such as the unclear toxicity in humans and the lack of thorough studies on reliable animal models. Still, their potential action is so appealing and the results so impressive that an outstanding number of papers is being published every year, with the consequence that any review on this topic becomes obsolete within a few months. Here we would like to report the latest findings on AuNPs research addressing all their functions as theranostic agents.

An updated overview on metal nanoparticles toxicity.

Although thousands of different nanoparticles (NPs) have been identified and synthesized to date, well-defined, consistent guidelines to control their exposure and evaluate their potential toxicity have yet to be fully established. As potential applications of nanotechnology in numerous fields multiply, there is an increased awareness of the issue of nanomaterials' toxicity among scientists and producers managing them. An updated inventory of customer products containing NPs estimates that they currently number over 5.000; ten years ago, they were one fifth of this. More often than not, products bear no information regarding the presence of NPs in the indicated list of ingredients or components. Consumers are therefore largely unaware of the extent to which nanomaterials have entered our lives, let alone their potential risks. Moreover, the lack of certainties with regard to the safe use of NPs is curbing their applications in the biomedical field, especially in the diagnosis and treatment of cancer, where they are performing outstandingly but are not yet being exploited as much as they could. The production of radical oxygen species is a predominant mechanism leading to metal NPs-driven carcinogenesis. The release of particularly reactive metal ions capable of crossing cell membranes has also been implicated in NPs toxicity. In this review we discuss the origin, behavior and biological toxicity of different metal NPs with the aim of rationalizing related health hazards and calling attention to toxicological concerns involved in their increasingly widespread use.

Environmental barium: potential exposure and health-hazards.

The relatively widespread presence of environmental barium is raising a growing public awareness as it can lead to different health conditions. Its presence in humans may produce several effects, especially among those chronically exposed from low to moderate doses. Barium accumulation can mainly occur by exposure in the workplace or from drinking contaminated water. However, this element is also assumed with the diet, mainly from plant foods. The average amount of barium intake worldwide and its geographical variation is little known due to the lack of research attention. Barium was never considered as an essential nutrient for humans, although it is undoubtedly naturally abundant enough and distinctive in its chemical properties that it might well have some biochemical function, e.g., for regulatory purposes, both in animals and plants. The information on the potential health effects of barium exposure is primarily based on animal studies and reported as comprising kidney diseases, neurological, cardiovascular, mental, and metabolic disorders. The present paper considers exposure and potential health concerns on environmental barium, giving evidence to information that can be used in future epidemiological and experimental studies.

Rh(I) Complexes in Catalysis: A Five-Year Trend.

Rhodium is one of the most used metals in catalysis both in laboratory reactions and industrial processes. Despite the extensive exploration on "classical" ligands carried out during the past decades in the field of rhodium-catalyzed reactions, such as phosphines, and other common types of ligands including N-heterocyclic carbenes, ferrocenes, cyclopentadienyl anion and pentamethylcyclopentadienyl derivatives, etc., there is still lively research activity on this topic, with considerable efforts being made toward the synthesis of new preformed rhodium catalysts that can be both efficient and selective. Although the "golden age" of homogeneous catalysis might seem over, there is still plenty of room for improvement, especially from the point of view of a more sustainable chemistry. In this review, temporally restricted to the analysis of literature during the past five years (2015-2020), the latest findings and trends in the synthesis and applications of Rh(I) complexes to catalysis will be presented. From the analysis of the most recent literature, it seems clear that rhodium-catalyzed processes still represent a stimulating challenge for the metalloorganic chemist that is far from being over.

Metal Toxicity and Speciation: A Review.

BACKGROUND: Essential metal ions play a specific and fundamental role in human metabolism. Their homeostasis is finely tuned, and any concentration imbalance in the form of deficiency or excess could lead to a progressive reduction and failure of normal biological function, to severe physiological and clinical outcomes, may eventually causing death. Conversely, non-essential metals are not necessary for life, and only noxious effects could arise after their exposure. Large environmental amounts of such chemicals come from both natural and anthropogenic sources, with the latter being predominant because of human activities. The dissipation of toxic metals contaminates water, air, soil, and food, causing a series of chronic and acute syndromes. OBJECTIVE: This review discusses the toxicity of non-essential metals considering their peculiar chemical characteristics, such as different forms, hard-soft character, oxidation states, binding capabilities, and solubility, which can influence their speciation in biological systems, and subsequently, the main cellular targets. Particular focus is given to selected toxic metals, major non-essential metals, or semimetals related to toxicity, such as mercury, lead, cadmium, chromium, nickel, and arsenic. In addition, we provide indications on the possible treatments/interventions for metal poisoning based on chelation therapy. CONCLUSION: Toxic metal ions can exert their peculiar harmful effects in several ways. They strongly coordinate with important biological molecules on the basis of their chemical- physical characteristics (mainly HSAB properties) or replace essential metal ions from their natural locations in proteins, enzymes, or hard structures, such as bones or teeth. Metals with redox properties could be key inducers of reactive oxygen species, leading to oxidative stress and cellular damage. Therapeutic detoxification, through complexation of toxic metal ions by specific chelating agents, appears an efficacious clinical strategy, mainly in acute cases of metal intoxication.

The Potential Clinical Properties of Magnesium.

A significant percentage of costs in pharmaceutical markets is devoted to supplements due to the confidence of consumers in the beneficial effects of these products. Magnesium is one of the supplements with enduring and increasing popularity. According to what is reported online, this metal ion can cure or prevent almost all kinds of diseases. This review aims at illustrating a series of scientifically demonstrated cases in which magnesium was used in clinical practice. Except for its ordinary use as antacid and laxative, other ascertained uses, reported in scientific literature, consist of helping to treat several diseases such as nocturnal leg cramps, pre-eclampsia, diabetes, depression, Parkinson's and Alzheimer's disease, hypertension, some types of arrhythmias, asthma, migraine headaches, epilepsy, cerebral haemorrhage, and stroke. However, many of these promising uses of magnesium require further studies to define the involved molecular mechanisms which should help establishing its uses in relation to the prolonged use of supplements.

Zinc Interactions with a Soluble Mutated Rat Amylin to Mimic Whole Human Amylin: An Experimental and Simulation Approach to Understand Stoichiometry, Speciation and Coordination of the Metal Complexes.

Islet amyloid polypeptide (IAPP) is a hormone co-secreted with insulin and zinc from pancreatic ß-cells. To overcome the low solubility of human IAPP, we characterized zinc complexes species formed with 1) a mutated form of rat-IAPP(1-37; R18 H) able to mimic the human IAPP, 2) the r-IAPP(1-37) and the IAPP(1-8) fragment. Stoichiometry, speciation and coordination features of zinc(II) complexes were unveiled by ESI-MS, potentiometry and NMR measurements combined with DFT and free-energy simulations. Mononuclear species start to form around pH 6; Zn2+ binds both His18 and N-amino terminus in rat-IAPP(1-37; R18 H). The in silico study allows us to assess not only a structured turn compact domain in r-IAPP(1-37) and r-IAPP(1-37; R18 H) featured by a different free energy barrier for the transition from the compact to elongated conformation upon the coordination of Zn2+ , but also to bring into light a coordination shell further stabilized by noncovalent interactions.

Exploring the Specificity of Rationally Designed Peptides Reconstituted from the Cell-Free Extract of Deinococcus radiodurans toward Mn(II) and Cu(II).

A series of five rationally designed decapeptides [DEHGTAVMLK (DP1), THMVLAKGED (DP2), GTAVMLKDEH (Term-DEH), TMVLDEHAKG (Mid-DEH), and DEHGGGGDEH (Bis-DEH)] have been studied for their interactions with Cu(II) and Mn(II) ions. The peptides, constructed including the most prevalent amino acid content found in the cell-free extract of Deinococcus radiodurans (DR), play a fundamental role in the antioxidant mechanism related to its exceptional radioresistance. Mn(II) ions, in complex with these peptides, are found to be an essential ingredient for the DR protection kit. In this work, a detailed characterization of Cu(II) systems was included, because Cu(II)-peptide complexes have also shown remarkable antioxidant properties. All peptides studied contain in their sequence coordinating residues that can bind effectively Mn(II) or Cu(II) ions with high affinity, such as Asp, Glu, and His. Using potentiometric techniques, NMR, EPR, UV-vis, and CD spectroscopies, ESI-MS spectrometry, and molecular model calculations, we explored the binding properties and coordination modes of all peptides toward the two metal ions, were able to make a metal affinity comparison for each metal system, and built a structural molecular model for the most stable Cu(II) and Mn(II) complexes in agreement with experimental evidence.

The essential metals for humans: a brief overview.

The human body needs about 20 essential elements in order to function properly and among them, for certain, 10 are metal elements, though for every metal we do need, there is another one in our body we could do without it. Until about 1950 poor attention was given to the so-called "inorganic elements" and while researches on "organic elements" (C, N, O and H) and organic compounds were given high priority, studies on essential inorganic elements were left aside. Base on current knowledge it is ascertained today that metals such as Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn and Mo are essential elements for life and our body must have appropriate amounts of them. Here a brief overview to highlight their importance and current knowledge about their essentiality.

A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays.

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clinical applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in analytical chemistry as well as in agricultural and environmental applications.

Medical Uses of Silver: History, Myths, and Scientific Evidence.

Silver has no biological role, and it is particularly toxic to lower organisms. Although several silver formulations employed in medicine in the past century are prescribed and sold to treat certain medical conditions, most of the compounds, including those showing outstanding properties as antimicrobial or anticancer agents, are still in early stages of assessment, that is, in vitro studies, and may not make it to clinical trials. Unlike other heavy metals, there is no evidence that silver is a cumulative poison, but its levels can build up in the body tissues after prolonged exposure leading to undesired effects. In this review, we deal with the journey of silver in medicine going from the alternative or do-it-yourself drug to scientific evidence related to its uses. The many controversies push scientists to move toward a more comprehensive understanding of the mechanisms involved.

Equilibrium studies of new bis-hydroxypyrone derivatives with Fe3+, Al3+, Cu2+ and Zn2.

This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+ < Cu2+ < Al3+ < Fe3+.

Ni(II) interaction with a peptide model of the human TLR4 ectodomain.

Ni(II) stimulates innate immunity via the direct binding to human Toll Like Receptor 4 (hTLR4), the bacterial lypopolysaccharide receptor. The binding is specific for humans and causes nickel contact allergy. The protein sequence analysis of hTLR4 revealed that the ectodomain, the region supposed to coordinate the metal ions, contains a histidine-rich motif that is not conserved among all organisms. To elucidate the role of each histidine residue on the protein-nickel binding, we examined the formation of Ni(II) complexes with the model peptide NH2-FQHSNRKQMSERSVFRSRRNRIYRDISHTHTR-COO-, which encompasses the sequence 429-460 of hTLR4. The amino acid sequence of the peptide has been modified by the substitution of some selected lipophilic residues (Leu and Phe) with hydrophilic residues (Arg), aiming at increasing the peptide hydro solubility of the protein fragment. Potentiometric, ultraviolet-visible (UV-vis), nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements demonstrate that the non-conserved histidines in the ectodomain cooperate in metal coordination and consequently enable the activation of the molecular mechanism of nickel hypersensitivity reaction.

Interaction of a chelating agent, 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one, with Al(III), Cu(II) and Zn(II) ions.

5-Hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one ligand, an iron chelator, was evaluated for its coordination ability toward Al(III), Cu(II) and Zn(II) ions by using potentiometric, NMR, EPR and UV-Vis techniques. The behavior of the ligand with the non-essential Al(III) ion has been examined, as well as its potential influence on the homeostatic equilibria of the essential Cu(II) and Zn(II) ions. Structural information on the complex formation equilibria have been obtained from 1D and 2D NMR study. The donor atoms involved in the coordination of Al(III), Cu(II) and Zn(II) ions are (O, O) the same as for Fe(III) at physiological pH value, even if from the complexation competition study the ligand appears to be more selective toward Fe(III) ions supporting that it can be used as an iron chelating agent. The involvement of N-donor atoms at high pH in Cu(II) coordination has been determined by using EPR and UV-Vis techniques.

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan.

We conducted a thorough study of Cu2+ complex formation equilibria with Irbesartan and Losartan, the two primary drugs for the cure of cardiovascular diseases, with the aim of recognising if these drugs could exert a chelating action towards Cu2+. We used different complementary techniques to gain a clear picture of the involved protonation and complexation equilibria. The low solubility in water of the ligands and of the formed metal complexes prevented the use of water as solvent, so we had to perform the measurements in mixed methanol-water solvents. Further, we studied the related equilibria with Zn2+ for evaluating a potential interference of this essential metal ion, largely present in biological fluids. Our study provided a strong evaluation of the formed complexes and of the relative stability constants. The binding of both metal ions takes place through the tetrazole moiety except for the Zn2+-Irbesartan system. In this last case, NMR measurements gave evidence of a tautomeric equilibrium involving the imidazole ring and the aliphatic chain. The estimated complexation model, and the related stability constants, allowed a speciation study in human plasma, based on a number of simplifying assumptions, which remarked that both drugs, Losartan and Irbesartan, could exert a chelating action, scavenging non-negligible amounts of Cu2+ from the organism.

Fluoroquinolones: A micro-species equilibrium in the protonation of amphoteric compounds.

The knowledge of the speciation of fluoroquinolones is of great actuality for the implications on the activity, bioavailability and pharmacokinetics. Literature reports a number of contrasting evaluations on the existence of tautomeric forms of mono-protonated species, described by a set of protonation micro-constants. Here the protonation sequence and the related protonation constants of four representative molecules are evaluated by a combined potentiometric-spectrophotometric method. The experimental observations necessary to differentiate between a protonation scheme represented by macro-constants alone, and the one that requires the introduction of a micro-protonation scheme, are clearly delineated based on a careful analysis of experimental data and of simulated models. The role of the medium was investigated and UV-vis spectra in water- methanol solution were analyzed. The existence of the zwitterionic species alone at physiological pH in water, and an increase of the relative amount of the neutral species with the lipophilicity of the medium were remarked. This surely affects the bioavailability of FQs, with the increase of the neutral species when the molecules approach the local lipophilic environment close to the cellular membranes. NMR studies allowed the attribution of the protonation sites of the different forms. Quantum chemical evaluation of all the possible existent forms with different protonation degrees and in different sites strongly substantiates the experimental results. The study of the relevant frontier molecular orbitals completed the detailed theoretical characterization of the species.