Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation

Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925

The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y2R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y2R antagonists leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1). One of these conjugates 98 displayed micromolar affinity for the hP2Y2R (pKd = 6.32 ± 0.10; n=17) using a bioluminescence energy transfer (BRET) assay. Confocal microscopy with this ligand revealed displaceable membrane labeling of astrocytoma cells expressing un-tagged hP2Y2R. These properties, make 98 one of the first tools for studying hP2Y2R distribution and organization

Exploring the use of new school buildings through post-occupancy evaluation and participatory action research

This paper presents the results of the development and testing of an integrated post-occupancy evaluation (POE) approach for teachers, staff, pupils and community members using newly constructed school buildings. It focusses on three cases of UK secondary schools, demonstrating how users can be inspired to engage with the problems of school design and energy use awareness. The cases provided new insights into the engagement of school teachers, staff and young people regarding issues of sustainability, management, functional performance and comfort. The integrative approach adopted in these cases provided a more holistic understanding of these buildings’ performance than could have been achieved by either observational or more traditional questionnaire-based methods. Moreover, the whole-school approach, involving children in POE, provided researchers with highly contextualised information about how a school is used, how to improve the quality of school experiences (both socially and educationally) and how the school community is contributing to the building's energy performance. These POE methods also provided unique opportunities for children to examine the social and cultural factors impeding the adoption of energy-conscious and sustainable behaviours

Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs

Ethical and methodological issues in engaging young people living in poverty with participatory research methods

This paper discusses the methodological and ethical issues arising from a project that focused on conducting a qualitative study using participatory techniques with children and young people living in disadvantage. The main aim of the study was to explore the impact of poverty on children and young people's access to public and private services. The paper is based on the author's perspective of the first stage of the fieldwork from the project. It discusses the ethical implications of involving children and young people in the research process, in particular issues relating to access and recruitment, the role of young people's advisory groups, use of visual data and collection of data in young people's homes. The paper also identifies some strategies for addressing the difficulties encountered in relation to each of these aspects and it considers the benefits of adopting participatory methods when conducting research with children and young people

Resourcing Scholar-Activism: Collaboration, Transformation, and the Production of Knowledge

In this article we offer a set of resources for scholar-activists to reflect on and guide their practice. We begin by suggesting that research questions should be triangulated to consider not only their scholarly merit but the intellectual and political projects the findings will advance and the research questions of interest to community and social movement collaborators

Towards transnational feminist queer methodologies

This article introduces the possibilities of transnational feminist queer research as seeking to conceptualise the transnational as a methodology composed of a series of flows that can augment feminist and queer research. Transnational feminist queer methodologies can contest long-standing configurations of power between researcher and researched, subject and object, academics and activists across places, typically those which are embedded in the hierarchies of the Global North/Global South. Beginning with charting our roots in, and routes through, the diverse arenas of transnational, feminist, participatory and queer methodologies, the article uses a transcribed and edited conversation between members of the Liveable Lives research team in Kolkata and Brighton, to start an exploration of transnational feminist queer methodologies. Understanding the difficult, yet constructive moments of collaborative work and dialogue, we argue for engagements with the multiplicities of ‘many-many' lives that recognise local specificities, and the complexities of lives within transnational research, avoiding creating a currency of comparison between places. We seek to work toward methodologies that take seriously the politics of place, namely by creating research that answers the same question in different places, using methods that are created in context and may not be ‘comparable'. Using a dialogue across the boundaries of activism/academia, as well as across geographical locations, the article contends that there are potentials, as well as challenges, in thinking ourselves through transnational research praxis. This seeks complexities and spatial nuances within as well as between places

Micro-resilience and justice: co-producing narratives of change

Significant lessons can be drawn from grassroots’ experiences of self-organizing to challenge the uneven distribution of resources and opportunities in cities. This paper examines the strategies of low-income dwellers living in squatted buildings in São Paulo, Brazil, and asks how resilience narratives can help one understand the agency of these micro-strategies across multiple scales. The city centre of São Paulo is a key site for housing movements to challenge spatial injustice in Brazil. In a context where housing for low-income groups is in short supply and characterized by highly skewed social and spatial distribution, squatted buildings have emerged since the 1990s as laboratories for alternative ways of producing the city. The paper draws from an action-research project investigating such occupations in São Paulo. Firstly, it explores the practices of individual and groups inhabiting a building known as Ocupação Marconi, focusing on its social production as a device for co-producing local resilience from the micro-scale. Secondly, it reflects on which forms of knowledge production might allow for putting such practices into focus, interrogating participatory action research as a means to facilitate resilience at scale

Ligand-directed covalent labelling of a GPCR with a fluorescent tag in live cells

© 2020, The Author(s). To study the localisation of G protein-coupled receptors (GPCR) in their native cellular environment requires their visualisation through fluorescent labelling. To overcome the requirement for genetic modification of the receptor or the limitations of dissociable fluorescent ligands, here we describe rational design of a compound that covalently and selectively labels a GPCR in living cells with a fluorescent moiety. We designed a fluorescent antagonist, in which the linker incorporated between pharmacophore (ZM241385) and fluorophore (sulfo-cyanine5) is able to facilitate covalent linking of the fluorophore to the adenosine A2A receptor. We pharmacologically and biochemically demonstrate irreversible fluorescent labelling without impeding access to the orthosteric binding site and demonstrate its use in endogenously expressing systems. This offers a non-invasive and selective approach to study function and localisation of native GPCRs

Co-production: towards a utopian approach

This article outlines how co-production might be understood as a utopian method, which both attends to and works against dominant inequalities. It suggests that it might be positioned ‘within, against, and beyond’ current configurations of power in academia and society more broadly. It develops this argument by drawing on recent research funded through the UK’s Connected Communities programme, led by the Arts and Humanities Research Council; and by attending to arguments from the field of Utopian Studies. It explores particular issues of power and control within the field of co-production, acknowledging that neoliberalism both constrains and co-opts such practice; and explores methodological and infrastructural issues such that its utopian potential might be realised