γ-Functional Iminiumthiolactones for Single or Double Modification of Peptides

Thiolactones have been extensively studied as efficient ligation strategy, yet, their reactivity towards bio-based building blocks remains limited. In this manuscript, we present their more reactive successors, iminiumthiolactones (ITL), which show superior reactivity towards amine-containing substrates. Based on the Traut’s reagent we synthesized several ITLs from glycidol precursors and investigated several orthogonal modification reactions. After performing basic calculations on our substrates to substantiate their predicted reactivity, we picked one of our derivatives (γ-allyl functional ITL 3b) to study model reactions and explore the orthogonality of its different reaction pathways. As a more challenging substrate, we further choose Lysozyme C to be modified with our γ-allyl ITL (3b) using low reactant concentrations (1 mM or 50 μM), near-neutral pH (7.4 or 8.0) and stoichiometric reactant ratios. Under the studied conditions, we successfully demonstrate that our ITL derivative exhibits orthogonal and enhanced reactivity in a single or double modification towards biological substrates. As such, we believe that γ-functional ITLs may open up promising opportunities to incorporate biological building blocks into existing functional molecules, polymeric frameworks and materials

γ-Functional Iminiumthiolactones for the Single and Double Modification of Peptides

Thiolactones (TL) can be readily incorporated into polymeric materials and have been extensively used as a ligation strategy despite their limited reactivity toward amine-containing substrates. Comparatively, iminiumthiolactones (ITL) are much more reactive, yet to this day, only the nonsubstituted ITL known as Traut’s reagent is commercially available and used. In this work, we advance current TL/ITL chemistry by introducing reactive side groups to the ITL heterocycle in the γ-position, which can be orthogonally modified without affecting the ITL heterocycle itself. To study the reactivity of γ-functional ITLs, we subject one of our derivatives (γ-allyl-functional ITL 3b) to model reactions with several peptides and a chosen protein (lysozyme C). Using mild reaction conditions, we successfully demonstrate that the γ-functional ITL exhibits orthogonal and enhanced reactivity in a single or double modification while introducing a new functional handle to the biological substrate. We believe that γ-functional ITLs will advance the original Traut chemistry and open promising opportunities for the bioconjugation of biological building blocks to existing functional molecules, polymers, and materials.ISSN:1043-1802ISSN:1520-481

Antibiotics and activity spaces: protocol of an exploratory study of behaviour, marginalisation and knowledge diffusion

Background Antimicrobial resistance (AMR) is a global health priority. Leading UK and global strategy papers to fight AMR recognise its social and behavioural dimensions, but current policy responses to improve the popular use of antimicrobials (eg, antibiotics) are limited to education and awareness-raising campaigns. In response to conceptual, methodological and empirical weaknesses of this approach, we study people’s antibiotic-related health behaviour through three research questions. RQ1: What are the manifestations and determinants of problematic antibiotic use in patients’ healthcare-seeking pathways? RQ2: Will people’s exposure to antibiotic awareness activities entail changed behaviours that diffuse or dissipate within a network of competing healthcare practices? RQ3: Which proxy indicators facilitate the detection of problematic antibiotic behaviours across and within communities? Methods We apply an interdisciplinary analytical framework that draws on the public health, medical anthropology, sociology and development economics literature. Our research involves social surveys of treatment-seeking behaviour among rural dwellers in northern Thailand (Chiang Rai) and southern Lao PDR (Salavan). We sample approximately 4800 adults to produce district-level representative and social network data. Additional 60 cognitive interviews facilitate survey instrument development and data interpretation. Our survey data analysis techniques include event sequence analysis (RQ1), multilevel regression (RQ1–3), social network analysis (RQ2) and latent class analysis (RQ3). Discussion Social research in AMR is nascent, but our unprecedented detailed data on microlevel treatment-seeking behaviour can contribute an understanding of behaviour beyond awareness and free choice, highlighting, for example, decision-making constraints, problems of marginalisation and lacking access to healthcare and competing ideas about desirable behaviour. Trial registration number NCT03241316; Pre-results