Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

Concentration or representation : the struggle for popular sovereignty

There is a tension in the notion of popular sovereignty, and the notion of democracy associated with it, that is both older than our terms for these notions themselves and more fundamental than the apparently consensual way we tend to use them today. After a review of the competing conceptions of 'the people' that underlie two very different understandings of democracy, this article will defend what might be called a 'neo-Jacobin' commitment to popular sovereignty, understood as the formulation and imposition of a shared political will. A people's egalitarian capacity to concentrate both its collective intelligence and force, from this perspective, takes priority over concerns about how best to represent the full variety of positions and interests that differentiate and divide a community

Common Gamma Chain Cytokines Promote Rapid In Vitro Expansion of Allo-Specific Human CD8+ Suppressor T Cells

Human CD8+ regulatory T cells, particularly the CD8+CD28− T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8+ T cells which results in significant expansions of donor-specific CD8+CD28− T suppressor cells in vitro. The expanded CD8+CD28− T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4+ T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8+CD28− T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation

Standardised Data on Initiatives – STARDIT: Beta Version

There is currently no standardised way to share information across disciplines about initiatives, including felds such as health, environment, basic science, manufacturing, media and international development. All problems, including complex global problems such as air pollution and pandemics require reliable data sharing between disciplines in order to respond efectively. Current reporting methods also lack information about the ways in which diferent people and organisations are involved in initiatives, making it difcult to collate and appraise data about the most efective ways to involve diferent people. The objective of STARDIT (Standardised Data on Initiatives) is to address current limitations and inconsistencies in sharing data about initiatives. The STARDIT system features standardised data reporting about initiatives, including who has been involved, what tasks they did, and any impacts observed. STARDIT was created to help everyone in the world fnd and understand information about collective human actions, which are referred to as ‘initiatives’. STARDIT enables multiple categories of data to be reported in a standardised way across disciplines, facilitating appraisal of initiatives and aiding synthesis of evidence for the most effective ways for people to be involved in initiatives

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Investigating and exploiting best practices in hit identification and hit to lead chemistry

Previously held under moratorium in Chemistry Department (GSK) from November 2016 until June 2019.A fragment-based drug discovery (FBDD) effort was carried out against the enzyme target BCATm. This resulted in elucidation of novel binding interactions against the enzyme. Several series of inhibitors were identified, these are the first known small molecule inhibitors of this enzyme. The compounds identified contained several examples which exhibited potent enzyme binding, excellent activity in a cellular assay and excellent DMPK profiles, making them high quality tools for target validation experiments. A comparative data analysis was carried out to compare the physicochemical properties of molecules discovered by FBDD, high throughput screening (HTS) and encoded library technology (ELT) against BCATm. This showed that the properties of the ELT derived molecules were consistently outside of the established areas of physicochemical properties for drugs and leads, whilst the HTS and FBDD derived compounds largely sat within the desired space. This analysis was extended to clinical candidates against a range of targets described in the literature as being discovered by a range of different techniques. Only slight trends for improved properties for FBDD derived molecules were observed. A phenotypic HTS hit against tuberculosis was identified to be acting through inhibition of the enzyme DprE1. This molecule had physicochemical properties which were far from the established limits for drug molecules. Through careful optimisation, using methodologies first established for FBDD, a lead series with much improved properties was derived. The lead molecules had potent inhibition of DprE1, were efficacious in halting the growth of Mycobacteria tuberculosis in vitro, had excellent DMPK properties and also showed good efficacy in in vivo models of tuberculosis.A fragment-based drug discovery (FBDD) effort was carried out against the enzyme target BCATm. This resulted in elucidation of novel binding interactions against the enzyme. Several series of inhibitors were identified, these are the first known small molecule inhibitors of this enzyme. The compounds identified contained several examples which exhibited potent enzyme binding, excellent activity in a cellular assay and excellent DMPK profiles, making them high quality tools for target validation experiments. A comparative data analysis was carried out to compare the physicochemical properties of molecules discovered by FBDD, high throughput screening (HTS) and encoded library technology (ELT) against BCATm. This showed that the properties of the ELT derived molecules were consistently outside of the established areas of physicochemical properties for drugs and leads, whilst the HTS and FBDD derived compounds largely sat within the desired space. This analysis was extended to clinical candidates against a range of targets described in the literature as being discovered by a range of different techniques. Only slight trends for improved properties for FBDD derived molecules were observed. A phenotypic HTS hit against tuberculosis was identified to be acting through inhibition of the enzyme DprE1. This molecule had physicochemical properties which were far from the established limits for drug molecules. Through careful optimisation, using methodologies first established for FBDD, a lead series with much improved properties was derived. The lead molecules had potent inhibition of DprE1, were efficacious in halting the growth of Mycobacteria tuberculosis in vitro, had excellent DMPK properties and also showed good efficacy in in vivo models of tuberculosis

Together or apart? Assessing brothers and sisters for permanent placement

Includes bibliographical references. Title from coverSIGLEAvailable from British Library Document Supply Centre- DSC:m03/23148 / BLDSC - British Library Document Supply CentreGBUnited Kingdo