Metallo therapeutics for COVID-19. Exploiting metal-based compounds for the discovery of new antiviral drugs

Introduction: The COVID-19 pandemic poses an unprecedented challenge for the rapid discovery of drugs against this life-threatening disease. Owing to the peculiar features of the metal centers that are currently used in medicinal chemistry, metallodrugs might offer an excellent opportunity to achieve this goal. Areas covered: Two main strategies for developing metal-based drugs against the SARS-CoV-2 are herein illustrated. Firstly, a few clinically approved metallodrugs could be evaluated in patients according to a ‘drug repurposing’ approach. To this respect, the gold drug auranofin seems a promising candidate, but some other clinically established metal compounds are worthy of a careful evaluation as well. On the other hand, libraries of inorganic compounds, featuring a large chemical diversity, should be screened to identify the most effective molecules. This second strategy might be assisted by a pathway-driven discovery approach arising from a preliminary knowledge of the mode of action, exploitable to inhibit the functional activities of the key viral proteins. Also, attention must be paid to selectivity and toxicity issues. Expert opinion: The medicinal inorganic chemistry community may offer a valuable contribution against COVID-19. The screening of metallodrugs’ libraries can expand the explored ‘chemical space’ and increase the chance of finding effective anti-COVID agents

A simulation code to assist designing space missions of the Airwatch type

The design of an Airwatch type space mission can greatly benefit from a flexible simulation code for establishing the values of the main parameters of the experiment. We present here a code written for this purpose. The cosmic ray primary spectrum at very high energies, the atmosphere modelling, the fluorescence yield, the photon propagation and the detector response are taken into account in order to optimize the fundamental design parameters of the experiment, namely orbit height, field of view, mirror radius, number of pixels of the focal plane, threshold of photo-detection. The optimization criterion will be to maximize counting rates versus mission cost, which imposes limits both on weight and power consumption. Preliminary results on signals with changing energy and zenith angle of incident particles are shown

Following the Problem Organisation: A Design Strategy for Engineering Emergence

To support the development of self-organising systems, we explain and rationalise the following architectural strategy: directly mapping the solution decomposition on the problem organisation and only relying on the problem abstractions for the design. We illustrate this with an example from swarm robotics

On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode

Similar biologic drug response regardless of radiographic status in axial spondyloarthritis : data from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis registry

Acknowledgements: We acknowledge Prof. Gary J. MacFarlane as chief investigator on the BSRBR-AS study. We are grateful to the staff of the BSRBR-AS register and to the recruiting staff at the clinical centres, details of which are available at www.abdn.ac.uk/bsrbr-as. H.M.O. designed the study proposal. X.M. analysed the data and wrote the manuscript, with significant input from all co-authors. G.T.J. is deputy chief investigator on the BSRBR-AS study and together with L.D. discussed results and provided input into drafts of the manuscript. The study was approved by the National Research Ethics Service Committee North East-County Durham and Tees Valley (reference 11/NE/0374) and informed consent was obtained from all participants. Funding: This work was supported by a research grant from the FOREUM Foundation for Research in Rheumatology. The BSRBR-AS is funded by the British Society for Rheumatology, which received funding for this from Pfizer, AbbVie and UCB. They have no input in determining the topics for analysis or work involved in undertaking it.Peer reviewedPublisher PD

Relativistic Heavy--Ion Collisions in the Dynamical String--Parton Model

We develop and extend the dynamical string parton model. This model, which is based on the salient features of QCD, uses classical Nambu-Got\=o strings with the endpoints identified as partons, an invariant string breaking model of the hadronization process, and interactions described as quark-quark interactions. In this work, the original model is extended to include a phenomenological quantization of the mass of the strings, an analytical technique for treating the incident nucleons as a distribution of string configurations determined by the experimentally measured structure function, the inclusion of the gluonic content of the nucleon through the introduction of purely gluonic strings, and the use of a hard parton-parton interaction taken from perturbative QCD combined with a phenomenological soft interaction. The limited number of parameters in the model are adjusted to $e^+e^-$ and $p$--$p$ data. Utilizing these parameters, the first calculations of the model for $p$--$A$ and $A$--$A$ collisions are presented and found to be in reasonable agreement with a broad set of data.Comment: 26 pages of text with 23 Postscript figures placed in tex

Synthesis and binding study of certain 6-arylalkanamides as molecular probes for cannabinoid receptor subtypes

Tetrahydrocannabinol and other mixed cannabinoid (CB) receptors CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects and psychomimetic actions, however, their potential for abuse have dampened enthusiasm for their therapeutic development. In an effort to refine a semi-rigid structural framework for CB(2) receptors binding, we designed novel compounds based on aromatic moiety and flexible linker with various amides mimicking the outlook of the endogenous anandamide which could provide as CB(2) receptor ligand. In this direction, we developed and synthesized new aryl or arylidene hexanoic acid amides and aryl alkanoic acid diamide carrying different head groups. These new compounds were tested for their affinities for human recombinant CB receptors CB(1) and CB(2) and fatty acid amide hydrolase. Although, the preliminary screening of these compounds demonstrated weak binding activity towards CB receptor subtypes at 10 µmole, yet this template still could serve up as probes for further optimization and development of affinity ligand for CB receptors