Macrocycle Therapeutics to Treat Life-threatening Diseases.

Polyphor's macrocycle platform led to the discovery of novel antibiotics addressing specifically Gramnegative bacteria by targeting outer membrane proteins. Furthermore, POL6014, an inhibitor of neutrophile elastase and balixafortide, a CXCR4 inhibitor have been discovered and developed from the platform. Currently a combination of balixafortide and eribulin is in Phase III clinical trial for the treatment of patients with advanced metastatic HER2-negative breast cancer.

Emerging peptide antibiotics with therapeutic potential.

This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.

Frontier Between Cyclic Peptides and Macrocycles.

This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features that potentially modulate cellular permeability. Examples range from exclusively peptidic structures like cyclosporin A or phepropeptins to compounds with mostly non-peptidic character, such as telomestatin or largazole. Furthermore, semisynthetic approaches and synthesis platforms to generate general and focused libraries of compounds at the interface of cyclic peptides and non-peptidic macrocycles are discussed.

Design, Properties and Recent Application of Macrocycles in Medicinal Chemistry.

Macrocyclic compounds have recently received increasing attention in drug discovery as these compounds offer the potential to modulate difficult targets and to access novel chemotypes. Approaches towards libraries of macrocyclic compounds based on modular organic synthesis and applications of these technology platforms to find and improve biologically active compounds are introduced in this minireview. Alternatively, lead compounds may be obtained by truncation and modification of macrocyclic natural products.

Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors.

Data from both our own and literature studies of the biochemistry and inhibition of influenza virus endonuclease was combined with data on the mechanism of action and the likely active site mechanism to propose a pharmacophore. The pharmacophore was used to design a novel structural class of inhibitors, some of which were found to have activities similar to that of known influenza endonuclease inhibitors and were also antiviral in cell culture.