Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as ‘ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.

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Corpora with specific entities and relationships annotated are essential to train and evaluate text-mining systems that are developed to extract specific structured information from a large corpus. In this paper we describe an approach where a named-entity recognition system produces a first annotation and annotators revise this annotation using a web-based interface. The agreement figures achieved show that the inter-annotator agreement is much better than the agreement with the system provided annotations. The corpus has been annotated for drugs, disorders, genes and their inter-relationships. For each of the drug-disorder, drug-target, and target-disorder relations three experts have annotated a set of 100 abstracts. These annotated relationships will be used to train and evaluate text-mining software to capture these relationships in texts.

Solute carrier (SLC) transporters are a superfamily of membrane bound proteins with over 300 identified members. These proteins serve as key regulators of cellular homeostasis by facilitating substrate entry and by‐product elimination across the plasma membrane. Dysregulation of SLC transporter function contributes to numerous diseases such as diabetes, Parkinson's disease and cancer. As SLCs are associated with a disease phenotype they are considered ‘druggable’ i.e., they can be modulated by drugs. Most current drugs that modulate SLC transporters do so by inhibiting transporter activity. For diseases in which decreased transporter activity leads to a potentially beneficial effect, high‐throughput screening (HTS) of large compound libraries using cell lines that overexpress the transporter of interest can be used to discover small molecule inhibitors. However, this is not necessarily a straightforward endeavor for all SLCs. The monocarboxylate transporters (MCTs) are a sub family of SLC transporters comprised of 14 members among which MCT1‐4 facilitate the bidirectional proton‐coupled co‐transport of monocarboxylates such as ketone bodies, pyruvate and lactate. MCT1 is of particular interest for its roles in cancer. Not only is it upregulated in the tumor microenvironment, but has also been identified as a key regulator of angiogenesis, invasion, migration and immune escape. Targeting this protein, MCT1/2 inhibitors are currently in clinical trials as anticancer therapies. More recently, MCT1 has also been identified as a potential drug target for metabolic and CNS disorders. Although MCT1 inhibitors have been identified, they lack selectivity for any given MCT isoform, and have exhibited select off target effects. Typical for this protein class, inhibitors for MCT1 have been difficult to identify, because traditionally, methods for their identification rely on the use of radiolabeled substrate tracking. In addition to the safety concerns associated with radioactivity, this methodology is also expensive and time consuming. Herein, we present a novel, non‐radioactive, cell‐based HTS‐compatible assay for identifying MCT1 inhibitors. Our method utilizes a cell line that endogenously expresses MCT1, and an MCT1 selective cytotoxic substrate, 3‐bromopyruvate (3BrPA). In our assay construct, MCT1 expressing cells are treated with potential MCT1 inhibitors, and then incubated with 3BrPA. In this paradigm, compounds that protect cells from cytotoxicity are identified as MCT1 inhibitors, because only cells treated with an inhibitor have interrupted MCT1 mediated transport and remain viable in the presence of 3BrPA. The screening method described here is robust, reproducible and HTS amenable. Moreover, it establishes a novel technique to identify chemical probes to study the therapeutic potential of MCTs while providing the conceptual framework for further assay development to identify inhibitors for other members of the SLC family. This abstract is from the Experimental Biology 2019 Meeting. There is no full text articl...

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson’s disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca2+ mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 μM at NTSR1 with full agonist behaviour (Emax = 100%), showing a higher efficacy and ~ 90-fold potency improvement compared to parent compound 1 (EC50 = 178 μM; Emax = 17%).