Evaluation of a non-nucleoside inhibitor of the RSV RNA-dependent RNA polymerase in translatable animals models.

Respiratory Syncytial Virus (RSV) causes severe respiratory infections and concomitant disease resulting in significant morbidity and mortality in infants, elderly, and immunocompromised adults. Vaccines, monoclonal antibodies, and small-molecule antivirals are now either available or in development to prevent and treat RSV infections. Although rodent and non-rodent preclinical animal models have been used to evaluate these emerging agents, there is still a need to improve our understanding of the pharmacokinetic (PK)-pharmacodynamic (PD) relationships within and between animal models to enable better design of human challenge studies and clinical trials.

Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor.

Molnupiravir maintains antiviral activity against SARS-CoV-2 variants and exhibits a high barrier to the development of resistance.

Molnupiravir, an oral prodrug of N-hydroxycytidine (NHC), previously demonstrated broad antiviral activity against multiple RNA viruses and has shown a high barrier to the development of resistance. Here, we present the antiviral activity of NHC against recent SARS-CoV-2 variants and the results of resistance selection studies to better understand the potential for viral resistance to NHC. NHC activity against SARS-CoV-2 variants omicron (BA.

Validation and Development of an Escherichia coli Riboflavin Pathway Phenotypic Screen Hit as a Small-Molecule Ligand of the Flavin Mononucleotide Riboswitch.

A riboflavin biosynthesis pathway-specific phenotypic screen using a library of compounds, all with unspecified antibiotic activity, identified one small molecule later named ribocil, for which intrinsic antibacterial activity against Escherichia coli was completely suppressed by addition of exogenous riboflavin to the bacterial growth medium. The ability of riboflavin to suppress the activity of ribocil, and further demonstration that ribocil inhibited riboflavin synthesis (IC = 0.3 μM), supported that a component of the riboflavin synthesis pathway was the molecular target.

Deposition of artificial radionuclides in sediments of Loch Etive, Scotland.

The nuclear fuel reprocessing plants on the Sellafield site (UK) have released low-level effluents into the Irish Sea under authorisation since 1952. This has led to the labelling of nearby offshore sediments with a range of artificial radionuclides. In turn, these sediments act as a long-term secondary source of both soluble and particle-associated radionuclides to coastal areas.

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry.

Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest in drugging ncRNA with small molecules. The recent discovery of ribocil, a structurally distinct synthetic mimic of the natural ligand of the flavin mononucleotide (FMN) riboswitch, has revealed the potential chemical diversity of small molecules that target ncRNA. Affinity-selection mass spectrometry (AS-MS) is theoretically applicable to high-throughput screening (HTS) of small molecules binding to ncRNA.

Nuclear reprocessing-related radiocarbon (C) uptake into UK marine mammals.

To evaluate the transfer of Sellafield-derived radiocarbon (C) to top predators in the UK marine environment, C activities were examined in stranded marine mammals. All samples of harbour porpoise (Phocoena phocoena) obtained from the Irish Sea showed C enrichment above background. Mammal samples obtained from the West of Scotland, including harbour porpoise, grey seals (Halichoerus grypus) and harbour seals (Phoca vitulina) showed C enrichment but to a lesser extent.

Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting.

Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli.

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (C) part 2: The West of Scotland.

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (C) were examined within the West of Scotland marine environment. The dissolved inorganic carbon component of seawater, enriched in C, is transported to the West of Scotland where it is transferred through the marine food web. Benthic and pelagic biota with variable life-spans living in the North Channel and Clyde Sea show comparable C activities.

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (C). Part 1. The Irish Sea.

Ecosystem uptake and transfer processes of Sellafield-derived radiocarbon (C) within the Irish Sea were examined. Highly variable activities in sediment, seawater and biota indicate complex C dispersal and uptake dynamics. All east basin biota exhibited C enrichments above ambient background while most west basin biota had C activities close to background, although four organisms including two slow-moving species were significantly enriched.

Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch.

Bacterial riboswitches are non-coding RNA structural elements that direct gene expression in numerous metabolic pathways. The key regulatory roles of riboswitches, and the urgent need for new classes of antibiotics to treat multi-drug resistant bacteria, has led to efforts to develop small-molecules that mimic natural riboswitch ligands to inhibit metabolic pathways and bacterial growth. Recently, we reported the results of a phenotypic screen targeting the riboflavin biosynthesis pathway in the Gram-negative bacteria Escherichia coli that led to the identification of ribocil, a small molecule inhibitor of the flavin mononucleotide (FMN) riboswitch controlling expression of this biosynthetic pathway.

Latest Quaternary palaeoceanographic change in the eastern North Atlantic based upon a dinoflagellate cyst event ecostratigraphy.

The analyses of dinoflagellate cyst records, from the latest Quaternary sediments recovered from DSDP Core 610A taken on the Feni Ridge in the southern Rockall Trough, and part of core MD01-2461 on the continental margin of the Porcupine Seabight in the eastern North Atlantic Ocean, has provided evidence for significant oceanographic change encompassing the Last Glacial Maximum (LGM) and part of the Holocene. This together with other published records has led to a regional evaluation of oceanographic change in the eastern North Atlantic over the past 68 ka, based upon a distinctive dinoflagellate event ecostratigraphy. These changes reflect changes in the surface waters of the North Atlantic Current (NAC), and perhaps the deeper thermohaline Atlantic Meridional Overturning Circulation (AMOC), driving fundamental regime changes within the phytoplanktonic communities.

Accumulation of Sellafield-derived radiocarbon ((14)C) in Irish Sea and West of Scotland intertidal shells and sediments.

The nuclear energy industry produces radioactive waste at various stages of the fuel cycle. In the United Kingdom, spent fuel is reprocessed at the Sellafield facility in Cumbria on the North West coast of England. Waste generated at the site comprises a wide range of radionuclides including radiocarbon ((14)C) which is disposed of in various forms including highly soluble inorganic carbon within the low level liquid radioactive effluent, via pipelines into the Irish Sea.

Selective small-molecule inhibition of an RNA structural element.

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors.

Ecological impacts of large-scale disposal of mining waste in the deep sea.

Deep-Sea Tailings Placement (DSTP) from terrestrial mines is one of several large-scale industrial activities now taking place in the deep sea. The scale and persistence of its impacts on seabed biota are unknown. We sampled around the Lihir and Misima island mines in Papua New Guinea to measure the impacts of ongoing DSTP and assess the state of benthic infaunal communities after its conclusion.