Multisubstrate adduct inhibitors: Drug design and biological tools

In drug discovery, different methods exist to create new inhibitors possessing satisfactory biological activity. The multisubstrate adduct inhibitor (MAI) approach is one of these methods, which consists of a covalent combination between analogs of the substrate and the cofactor or of the multiple substrates used by the target enzyme. Adopted as the first line of investigation for many enzymes, this method has brought insights into the enzymatic mechanism, structure, and inhibitory requirements. In this review, the MAI approach, applied to different classes of enzyme, is reported from the point of view of biological activity.

Sticks, Stones and Words: Emotional Harm and the English Criminal Law

This article discusses the rule that criminal liability does not normally attach for the causing of emotional harm or mental distress in the absence of proof of a 'recognised psychiatric injury'. It considers what is involved in the diagnosis of psychiatric injury, and to what extent the difference between such injury and 'ordinary' mental distress is one of degree rather than one of kind. It reviews the situations in which the law already criminalises the infliction of emotional harm without proof of psychiatric injury, and assesses the policy arguments for drawing the distinction in the normal case. The article concludes that the law can and should adopt a more flexible approach to cases of this sort.

Recent Advances in Antidiabetic Drug Therapies Targeting the Enteroinsular Axis

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e. g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA.