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The 'Safety in Numbers' (SiN) effect proposes that when the volume of cycling traffic increases, the number of crashes increases less (relative to the cycling volume). A recent meta-analysis supported the general idea of a SiN effect, but also highlighted the heterogeneity of its strength, also see). The authors of this meta-study conclude that the SiN effect is strenger at the macro-level than at the micro-level, but bears no clear relationship to the quality of the cycling infrastructure. The mechanisms producing the SiN effect are still unknown. Possible explanations are (i) that safer street regulations and designs are more likely to ex.ist in societies with more wallcing and bicycling; (ii) changes in the behavior of people walking or bicycling; or (iii) changes in behavior of drivers. However, all of these explanations have their shortcomings. Additionally, some authors have argued that an increase in the number of crashes cannot be ruled out due to the increasing numbe:r of inexpe:rienced or particularly risk-taking cyclists. The:re appears to be little research on the question whether and how the SiN effect may be linked to specific road types featuring different combinations of speed zones and cycling infrastructures. Furthermore, the base rate of cyclists (i.e. the cycling volume) is a highly relevant factor when investigating the distribution of crashes throughout different road types [6]. In our research, we thus use a GIS-based approach aimed at testing the relation between the cycling volume and the number of crashes involving cyclists for roads featuring different speed zones and cycling infrastructures.

The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogs of FK506 called SAFit1 and SAFit2, the most advanced FKBP51 inhibitors so far, were shown to be highly selective for FKBP51 over its closest homolog FKBP52, allowing the proof-of-concept studies in animal models. However, the SAFit ligands show several liabilities in their drug-like parameters and further modifications are needed for future drug developments. Due to the shallow binding site of FKBP51, the creation of low molecular mass inhibitors based on the SAFit scaffold remained unfruitful. Here, we pursued a different strategy and chose a structure-based approach to implement the SAFit scaffold into a macrocyclic framework. Macrocycles are a compound class known to be able to cope with difficult drug targets and key drug properties like solubility, metabolic stability, and oral bioavailability often benefit from the cyclization of linear ligands. Hence, we designed a synthesis strategy to vary linkage, linker length and functionalization and synthesized the first FKBP51-selective, macrocyclic ligand library. All 33 macrocycles retained high FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively. Furthermore, we present the synthesis of multi-gram amounts of SAFit2 as well as an inactive SAFit2 diastereomer and deuterated SAFit analogs. These compounds will contribute to high-quality research on FKBP51 in cellular and animal models and help to decipher its biochemical and biological role.

In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.

In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.