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Modern approaches in metallodrug research focus on compounds that bind protein targets rather than DNA. However, the identification of protein targets and binding sites is challenging. Using intact mass spectrometry and proteomics, we investigated the binding of the antimetastatic agent RAPTA-C to the model proteins ubiquitin, cytochrome c, lysozyme, and myoglobin. Binding to cytochrome c and lysozyme was negligible. However, ubiquitin bound up to three Ru moieties, two of which were localized at Met1 and His68 as [Ru(cym)], and [Ru(cym)] or [Ru(cym)(PTA)] adducts, respectively. Myoglobin bound up to four [Ru(cym)(PTA)] moieties and five sites were identified at His24, His36, His64, His81/82 and His113. Collision-induced unfolding (CIU) studies via ion-mobility mass spectrometry allowed measuring protein folding as a function of collisional activation. CIU of protein-RAPTA-C adducts showed binding of [Ru(cym)] to Met1 caused a significant compaction of ubiquitin, likely from N-terminal S-Ru-N chelation, while binding of [Ru(cym)(PTA)] to His residues of ubiquitin or myoglobin induced a smaller effect. Interestingly, the folded state of ubiquitin formed by His functionalization was more stable than Met1 metalation. The data suggests that selective metalation of amino acids at different positions on the protein impacts the conformation and potentially the biological activity of anticancer compounds., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Mass spectrometry (MS) is an analytical technique for molecule identification that can be used for investigating protein-metal complex interactions. Once the MS data is collected, the mass spectra are usually interpreted manually to identify the adducts formed as a result of the interactions between proteins and metal-based species. However, with increasing resolution, dataset size, and species complexity, the time required to identify adducts and the error-prone nature of manual assignment have become limiting factors in MS analysis. AdductHunter is a open-source web-based analysis tool that  automates the peak identification process using constraint integer optimization to find feasible combinations of protein and fragments, and dynamic time warping to calculate the dissimilarity between the theoretical isotope pattern of a species and its experimental isotope peak distribution. Empirical evaluation on a collection of 22 unique MS datasetsshows fast and accurate identification of protein-metal complex adducts in deconvoluted mass spectra., (© 2024. The Author(s).)

Metal complexes bind to a wide variety of biomolecules and the control of the reactivity is essential when designing anticancer metallodrugs with a specific mode of action in mind. In this study, we used the highly cytotoxic compound [RuII(cym)(8-HQ)Cl] (cym = η6-p-cymene, 8-HQ = 8-hydroxyquinoline), the more inert derivative [RuII(cym)(8-HQ)(PTA)](SO3CF3) (PTA = 1,3,5-triaza-7-phosphaadamantane), and [RuII(cym)(PCA)Cl]Cl (PCA = pyridinecarbothioamide) as a complex with a different coordination environment about the Ru center and investigated their stability, interactions with proteins, and behavior in medium (αMEM) and human serum by capillary zone electrophoresis. The developed method was found to be robust and provides a quick and low-cost technique to monitor the interactions of such complexes with biomolecules. Each complex was found to behave very differently, emphasizing the importance of the choice of ligands and demonstrating the applicability of the developed method. Additionally, the human serum albumin binding site preference of [RuII(cym)(8-HQ)Cl] was investigated through displacement studies, revealing that the compound was able to bind to both sites I and site II, and the type of adducts formed with transferrin was determined by mass spectrometry., (© The Author(s) 2022. Published by Oxford University Press.)

The current coronavirus disease 2019 (COVID-19) pandemic has put significant strain on all aspects of health care delivery, including palliative care services. Given the high mortality from this disease, particularly in the more vulnerable members of society, it is important to examine how best to deliver a high standard of end-of-life care during this crisis. This case series collected data from two acute hospitals examining the management of patients diagnosed with COVID-19 who subsequently died (n = 36) and compared this with national and local end-of-life audit data for all other deaths. Our results demonstrated a shorter dying phase (38.25 hours vs. 74 hours) and higher rates of syringe driver use (72% vs. 33% in local audits), although with similar average mediation doses. Of note was the significant heterogeneity in the phenotype of deterioration in the dying phase, two distinct patterns emerged, with one group demonstrating severe illness with a short interval between symptom onset and death and another group presenting with a more protracted deterioration. This brief report suggests a spectrum of mode of dying. Overall, the cohort reflects previously described experiences, with increased frailty (median Clinical Frailty Scale score of 5) and extensive comorbidity burden. This brief report provides clinicians with a contemporaneous overview of our experience, knowledge, and pattern recognition when caring for people with COVID-19 and highlights the value of proactive identification of patients and risk of deterioration and palliation., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. All rights reserved.)