Michael J.

8-Hydroxy-dihydroergotamine is the major human metabolite of the anti-migraine drug dihydroergotamine and is required, along with a stable isotope-labelled derivative, to aid metabolic studies. An efficient, scalable synthesis of the unlabelled compound is described via the coupling of dihydrolysergic acid to the tricyclic amino compound (2R,5S,8R,10aS,10bS)-2-amino-5-benzyl-10b-hydroxy-8-methoxy-2-methyltetrahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-3,6(2H,5H)-dione. The tricycle was obtained by a convergent synthesis combining precursors from suitably protected L-glutamic acid and L-phenylalanine, and 2-bromo-2-methylmalonic acid. For the labelled molecule, the tricyclic precursor contained a pentadeutero benzyl group derived from [2,3,4,5,6-2H5]L-phenylalanine. Considerable experimentation was required to achieve optimal activation of dihydrolysergic acid for efficient amide formation with the tricycle’s amino function affording 8-methoxy-dihydroergotamine. The stereochemical integrity of an intermediate in this synthesis, ethyl (2R,5S,8R,10aS)-5-benzyl-10b-hydroxy-8-methoxy-2-methyl-3,6-dioxooctahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylate, was validated by crystal structure analysis. Acid-catalysed hydrolysis of 8-methoxy-dihydroergotamine gave 8-hydroxy-dihydroergotamine. Pentadeuterated 8-hydroxy-dihydroergotamine was obtained in an analogous manner from [2,3,4,5,6-2H5]L-phenylalanine. Both 8-hydroxy-dihydroergotamine and its 2H5-derivative were obtained as an equilibrating mixture of C-8 epimers (diastereomers), with the major isomer having (R)-configuration according to 1H NMR analysis. The syntheses described enable the routine synthesis of 50–100 mg quantities of each target molecule.

SARS-CoV-2 vaccination or infection may not protect from future novel coronavirus outbreaks. Although several drugs targeting essential coronavirus proteins are broadly effective, the error-prone coronavirus RNA-dependent RNA polymerase and a rapid viral replication cycle mean that drug resistance will likely emerge. Small molecules that target sequence-stable host proteins could offer more durable pan-coronavirus activity. Here, we show that the well-tolerated and orally bioavailable small molecule SH-BC-893 protects from endosomal, but not plasma membrane, entry by diverse coronavirus strains. SH-BC-893 alters endolysosomal trafficking similar to PIKfyve inhibitors and, like hydroxychloroquine, reduces cathepsin L activity. While all three compounds block endosomal entry mediated by coronavirus spike proteins in vitro, PIKfyve inhibitors and chloroquine derivatives are ineffective or even increase viral titer in vivo. In contrast, SH-BC-893 reduced viral titer in the lungs of mice infected intranasally with the LD50 of the MHV-1 coronavirus by 3 logs. Thus, poor in vivo outcomes when using apilimod or chloroquine as anti-virals likely reflect pharmacologic limitations of these compounds rather than a flawed therapeutic strategy. We anticipate that SH-BC-893 or optimized analogs with similar tissue pharmacology could control infections by novel coronaviruses, particularly if given in combination with TMPRSS2 inhibitors to block entry at the plasma membrane, an obvious escape pathway. Because it targets host rather than viral proteins, SH-BC-893 might also block infection by many other viruses that enter via endosomal pathways: orthomyxoviruses (influenza), filoviruses (Ebola, Marburg), flaviviruses (Dengue, Zika, and West Nile), alphaviruses (Chikungunya) rhabdoviruses (rabies), and bunyaviruses (Hantaan or Sin Nombre). In sum, further evaluation of SH-BC-893 and/or optimized analogs as potential pan-antiviral agents is merited.

Birnessite, a layered-structure MnO2, is an earth-abundant functional material with potential for various energy and environmental applications, su...

Little is known about how values emerge, evolve and affect people’s relation with their natural environment. A study now sheds light on the influence of the institutions of European colonization on present-day values towards wildlife in the Americas.

Semaglutide is a glucagon-like peptide-1 (GLP-1) with a potential gerotherapeutic role. This post-hoc analysis of a phase 2b trial in adults with HIV associated lipohypertrophy reveals that semaglutide can modulate epigenetic biomarkers of aging.

Semaglutide-induced weight loss is shown to depend on Gs-coupled signalling in GLP1R-expressing hindbrain neurons, with a critical role for cAMP in mediating neuronal activation and downstream effects.

Food allergy is a major public health concern. Risk assessment and risk management of food allergens are often dependent on the analytical detection and quantification of allergens. Equally important is a clear reporting of the resulting data to avoid a lack of transparency and thus to protect sensitive consumers and support EU regulatory compliance. The European Network of Food Allergen Detection Laboratories (ENFADL) established a Task Force to develop best-practice guidance for reporting allergen testing results. A survey of 25 laboratories from 19 EU Member and EFTA States revealed examples of good practice. However, there was substantial variation in metadata provision, especially for recovery, conversion factors, measurement uncertainty, and detection limits. Qualitative methods (mainly PCR) typically reported presence/absence together with a limit of detection (LOD), while quantitative methods (predominantly ELISA) showed greater variability in the format and inclusion of key parameters. Drawing on the survey data and recommended best practices by ILSI-Europe and the ALLKITS project, the Task Force defined minimum reporting requirements, detailed in Table 5, to promote that results are interpretable, comparable as far as possible, and fit for regulatory, contractual, and risk assessment purposes.

The concepts of “climate change worry” and “climate change anxiety” are often used interchangeably in climate research, but they may reflect distinct emotional responses to climate change, which could potentially have different implications for public mental health. This research brief aims to empirically examine the differences between these two constructs by comparing their associations with key indicators of subjective wellbeing. Using survey data from 32 countries (N = 12,246), we compared how strongly climate change worry and state climate anxiety were each associated with subjective wellbeing, as measured by the WHO-5 Wellbeing Index and life satisfaction. State climate anxiety showed stronger associations with both WHO-5 Wellbeing Index and life satisfaction than climate change worry. This underscores the importance of treating the two as distinct emotional responses, each with different implications for public wellbeing. These insights are especially relevant for policymakers and climate communicators, who must carefully consider the emotional tone of climate messaging to foster constructive engagement while safeguarding the psychological wellbeing of the public.