Makrocyclische Peptide mit dem Zielprotein angepassten Kohlenwasserstoffbrücken: Inhibitoren einer pathogenen Protein-Protein-Wechselwirkung

Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis. Show more

The Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) has viewed with concern the decreasing investment by major pharmaceutical companies in antimicrobial research and development. Although smaller companies are stepping forward to address this gap, their success is uncertain. The IDSA proposed legislative and other federal solutions to this emerging public health problem in its July 2004 policy report "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews." At this time, the legislative response cannot be predicted. To emphasize further the urgency of the problem for the benefit of legislators and policy makers and to capture the ongoing frustration our clinician colleagues experience in their frequent return to an inadequate medicine cabinet, the AATF has prepared this review to highlight pathogens that are frequently resistant to licensed antimicrobials and for which few, if any, potentially effective drugs are identifiable in the late-stage development pipeline. Show more

Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads--and how criteria applied to these may differ from conventional small-molecule drugs--are summarized. Show more