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.

Sexual division of antibacterial resource defence in breeding burying beetles, Nicrophorus vespilloides

A key component of parental care involves defending resources destined for offspring from a diverse array of potential interspecific competitors, such as social parasites, fungi and bacteria. 2. Just as with other aspects of parental care, such as offspring provisioning or brood defence, sexual conflict between parents may arise over how to share the costs of this form of care. There has been little previous work, however, to investigate how this particular burden might be shared. 3. Here, we describe a hitherto uncharacterized form of parental care in burying beetles Nicrophorus vespilloides, a species which prepares carrion for its young and faces competition from microbes for this resource. We found that parents defend the carcass with antibacterial anal exudates, and that the antibacterial activity of these exudates is only upregulated following the discovery of a corpse. At the same time, phenoloxidase activity in the anal exudates is downregulated, indicating parallels with the internal insect immune system. 4. In unmanipulated breeding pairs, females had higher antibacterial activity in their anal exudates than males, suggesting sex-specific roles in this aspect of parental care. 5. When we experimentally widowed males, we found that they increased levels of antibacterial activity in their anal exudates. Experimentally widowing females, however, led them to decrease levels of antibacterial activity in their anal exudates. Widowed beetles of each sex thus produced anal exudates of comparable antibacterial activity. We suggest that this flexible division of antibacterial activity may be coordinated by Juvenile Hormone. © 2009 British Ecological Society.

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.