Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand - LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties

Progress in the development of non-​BET bromodomain chemical probes

The bromodomain and extra terminal (BET) family of bromodomains have been the focus of extensive research, leading to the development of many potent, selective chem. probes and recent clinical assets. The profound biol. associated with BET bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. However, the BET family represents just eight of the at least 56 human bromodomains identified to date. Until recently, there has been significantly less interest in non-​BET bromodomains, leaving a vast area of research and the majority of this new target class yet to be thoroughly investigated. It has been widely reported that several non-​BET bromodomain containing. proteins are associated with various diseases including cancer and HIV. Therefore, the development of chem. probes for non-​BET bromodomains will facilitate elucidation of their precise biol. roles and potentially lead to the development of new medicines. This review summarises the progress made towards the development of non-​BET bromodomain chem. probes to date. In addn., we highlight the potential for future work in this new and exciting area

Cyclic and macrocyclic peptides as chemical tools to recognise protein surfaces and probe protein-protein interactions

Targeting protein surfaces and protein–protein interactions (PPIs) with small molecules is a frontier goal of chemical biology and provides attractive therapeutic opportunities in drug discovery. The molecular properties of protein surfaces, including their shallow features and lack of deep binding pockets, pose significant challenges, and as a result have proved difficult to target. Peptides are ideal candidates for this mission due to their ability to closely mimic many structural features of protein interfaces. However, their inherently low intracellular stability and permeability and high in vivo clearance have thus far limited their biological applications. One way to improve these properties is to constrain the secondary structure of linear peptides by cyclisation. Herein we review various classes of cyclic and macrocyclic peptides as chemical probes of protein surfaces and modulators of PPIs. The growing interest in this area and recent advances provide evidence of the potential of developing peptide‐like molecules that specifically target these interactions