Editorial
Introduction to ‘Synthesis and chemical biology of macrocycles’
Gong Chen, Monika Raj and Andrei Yudin introduce the RSC Chemical Biology themed collection on the ‘Synthesis and chemical biology of macrocycles’.
Review Article
Peptide/protein-based macrocycles: from biological synthesis to biomedical applications
Peptide- and protein-based macrocycles have been biologically synthesized and evolved with enhanced stability and high bioactivity that are superior to their linear counterparts for diverse biomedical applications.
Review Article
Cyclic peptide drugs approved in the last two decades (2001–2021)
In this mini-review, we summarized the chemical structure, mechanism of action, and metabolism of cyclic peptide drugs approved in the last two decades. We also examined factors important for the development and utilization in clinical situations.
Communication
Targeted disruption of PKC from AKAP signaling complexes
We report the development of AKAP derived, conformationally constrained peptides designed to probe AKAP-localized PKC. The lead peptides, CSTAD5 and CSTAD6 permeate cells, bind PKC, disrupt its scaffolding by AKAPs to inhibit its scaffolded activity.
Paper
Landscaping macrocyclic peptides: stapling hDM2-binding peptides for helicity, protein affinity, proteolytic stability and cell uptake
Surveying macrocycles for mimicking a helical tumor suppressor protein, resisting breakdown by proteases, and entering cancer cells.
Paper
Navigating complex peptide structures using macrocycle conformational maps
Identification of turn motifs that are stabilized by hydrogen bonds can be useful in describing the conformation of peptides. Herein, we describe “higher-order” ϕ/ψ plots termed macrocycle conformational maps (MCMs) as a tool to evaluate and compare the conformations of related macrocycles.
Paper
Structural impact of thioamide incorporation into a β-hairpin
NMR studies of macrocyclic β-hairpin model systems demonstrate that thioamides can be tolerated at both hydrogen bond donor and hydrogen bond acceptor positions.
Paper
Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions
A conjugate addition/ring expansion (CARE) cascade reaction sequence is reported that enables medium-sized ring and macrocyclic bis-lactams to be prepared from primary amines and cyclic imides.
Paper
Inner residues of macrothiolactone in autoinducer peptides I/IV circumvent spontaneous S-to-O acyl transfer to the upstream serine residue
In AIP-I/IV, single Gly mutation at the thiolactone induces S-to-O acyl shift to yield a corresponding ring-expanded lactone form.
Paper
Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors
mRNA display leads to the identification of a macrocyclic peptide inhibitor with a unique binding mode to MDM2, a negative regulator of the tumor suppressor p53. Conjugation to a cell-penetrating peptide allows in cellulo evaluation of inhibition.
Paper
Entropy of stapled peptide inhibitors in free state is the major contributor to the improvement of binding affinity with the GK domain
The significant improvement in the binding affinity of the stapled peptide to the PSD-95 GK domain is mostly contributed by the reduction in the entropy penalty of the stapled peptide due to the restriction in the α-helical structure by stapling in the free state.
About this collection
Macrocycles are an important class of compounds with a long-recognised, significant role in chemical biology and drug discovery. This themed collection offers a collection of articles that showcase the ongoing interest in the chemical biology of macrocycles. Recent years have witnessed the development of new synthetic and biological strategies to construct large rings composed of amino acid residues. In addition, significant progress has been made in efforts to understand and predict the properties of macrocycles. We have collected contributions that are representative of the tremendous promise and pace of growth in this area.
The work in this collection covers all areas of the synthesis and chemical biology of macrocycles, including new synthetic and biosynthetic pathways for synthesis of diverse range of macrocycles; peptide and peptidomimetics macrocycles; design and synthesis of macrocycles for biological and medicinal applications; cell permeable macrocycles for targeting intracellular proteins; structural studies of macrocycles to expand the conformational drug space, and much more. Taken together, the papers collected in this themed collection represent the state of the art in macrocycles and highlight work at the interface of chemistry and biology.