https://pubs.rsc.org/en/content/articlepdf/2013/cc/c3cc41143e

Exploration of the medical periodic table: towards new targets

Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26-32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. The primary functions that direct coronavirus RNA synthesis and processing reside in nonstructural protein (nsp) 7 to nsp16, which are cleavage products of two large replicase polyproteins translated from the coronavirus genome. Significant progress has now been made regarding their structural and functional characterization, stimulated by technical advances like improved methods for bioinformatics and structural biology, in vitro enzyme characterization, and site-directed mutagenesis of coronavirus genomes. Coronavirus replicase functions include more or less universal activities of plus-stranded RNA viruses, like an RNA polymerase (nsp12) and helicase (nsp13), but also a number of rare or even unique domains involved in mRNA capping (nsp14, nsp16) and fidelity control (nsp14). Several smaller subunits (nsp7-nsp10) act as crucial cofactors of these enzymes and contribute to the emerging "nsp interactome." Understanding the structure, function, and interactions of the RNA-synthesizing machinery of coronaviruses will be key to rationalizing their evolutionary success and the development of improved control strategies.

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing.

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism characterised by pathological copper accumulation. WD is caused by mutations in the ATP7B gene, which encodes a transmembrane copper-transporting ATPase, leading to copper overload in the liver, brain and other organs. The clinical course of WD can vary in severity but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed based on diagnostic algorithms incorporating clinical symptoms and signs, measures of copper metabolism and DNA analysis. Available treatments include chelators and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials and genetic therapies are being tested in animal models. With early treatment, the prognosis of disease is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with this disorder.

/pdf/nature-reviews-disease-primers-article-wilson-disease-9ugo2qe4vl.pdf

Nature Reviews Disease Primers article: Wilson disease

Cathy S. Cutler,*,† Heather M. Hennkens,† Nebiat Sisay,†,‡ Sandrine Huclier-Markai, and Silvia S. Jurisson‡ †University of Missouri Research Reactor Center, Columbia, Missouri 65211, United States ‡Department of Chemistry, University of Missouri, Columbia, Missouri 65211, United States Laboratoire Subatech, UMR 6457, Ecole des Mines de Nantes/Universite de Nantes/CNRS-IN2P3, 4 Rue A. Kastler, BP 20722, F-44307 Nantes Cedex 3, France

Radiometals for Combined Imaging and Therapy

Metals such as mercury, arsenic, copper and silver have been used in various forms as antimicrobials for thousands of years with until recently, little understanding of their mode of action. The discovery of antibiotics and new organic antimicrobial compounds during the twentieth century saw a general decline in the clinical use of antimicrobial metal compounds, with the exception of the rediscovery of the use of silver for burns treatments and niche uses for other metal compounds. Antibiotics and new antimicrobials were regarded as being safer for the patient and more effective than the metal-based compounds they supplanted. Bacterial metal ion resistances were first discovered in the second half of the twentieth century. The detailed mechanisms of resistance have now been characterized in a wide range of bacteria. As the use of antimicrobial metals is limited, it is legitimate to ask: are antimicrobial metal resistances in pathogenic and commensal bacteria important now? This review details the new, rediscovered and 'never went away' uses of antimicrobial metals; examines the prevalence and linkage of antimicrobial metal resistance genes to other antimicrobial resistance genes; and examines the evidence for horizontal transfer of these genes between bacteria. Finally, we discuss the possible implications of the widespread dissemination of these resistances on re-emergent uses of antimicrobial metals and how this could impact upon the antibiotic resistance problem.

Bacterial antimicrobial metal ion resistance.

Biocoordination chemistry of bismuth : Recent advances

Synthesis, characterization and DNA-binding properties of La(III) complex of chrysin.

structures exhibit unique ‘‘partially-opened’’ conformations between those of the apo-hTF and holo-hTF. Fe(III) and Bi(III) in the N-lobe coordinate to, besides anions, only two (Tyr95 and Tyr188) and one (Tyr188) tyrosine residues, respectively, in contrast to four residues in the holo-hTF. The C-lobe of both structures are fully closed with iron coordinating to four residues and a carbonate. The structures of hTF observed here represent key conformers captured in the dynamic nature of the transferrin family proteins and provide a structural basis for understanding the mechanism of metal uptake and release in transferrin families.

/pdf/iron-and-bismuth-bound-human-serum-transferrin-reveals-a-2spp41rlnr.pdf

Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

Hold tight: Bismuth complexes including ranitidine bismuth citrate effectively inhibit the nucleoside triphosphate hydrolase and DNA unwinding activities of the SARS coronavirus (SCV) helicase and dramatically reduce SCV replication levels in infected cells. This suggests that bismuth‐based drugs should be further evaluated for the treatment of SCV infections in vivo. ss=single‐stranded DNA, ds=duplex DNA.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200701021

Bismuth Complexes Inhibit the SARS Coronavirus

https://www.rsc.org/suppdata/cc/b7/b709515e/b709515e.pdf

Nan Yang

Papers

Biocoordination chemistry of bismuth : Recent advances

Synthesis, characterization and DNA-binding properties of La(III) complex of chrysin.

Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

Bismuth Complexes Inhibit the SARS Coronavirus

Inhibition of SARS coronavirus helicase by bismuth complexes