Bioactive and Membrane‐Permeable Cyclic Peptide Natural Products

Single-Shot Flow Synthesis of D-Proteins for Mirror-Image Phage Display

“…Because they are not recognized by native L-proteases, D peptides display uncommonly long in vivo half lives 54 , and as a result are a privileged peptide drug scaffold. In addition, masking of amide hydrogens through macrocyclization as exemplified by the peptide natural products cyclosporin A 55 , kalata-b1 56 , and the candidate PCSK9 inhibitor MK-0616 57 , can impart potent cell permeability. These favorable properties are leading to a renewed interest in these scaffolds for drug discovery efforts, and the rapid generation of macrocyclized D peptide ligands to novel protein targets by AFPS reported here offers a unique approach to advance this emerging field of study.…”

Accurate de novo design of membrane-traversing macrocycles

“…Peptides with intrinsic membrane permeability can access intracellular drug targets, translocate across intestinal epithelial cells enabling oral delivery, and penetrate the blood-brain barrier by traversing brain microvascular endothelial cells. Naturally occurring macrocycles, such as cyclosporine A and griselimycin, suggest potential mechanisms for permeability of large macrocycles that are beyond the traditional “rule of five” (Ro5) ( Bockus and Lokey, 2017 ; Bockus et al., 2015 ; Hewitt et al., 2015 ; Nielsen et al., 2017 ). However, adapting the insights from a few naturally permeable macrocycles to develop new membrane-permeable peptides of diverse shapes and sizes has proven very difficult.…”

Insights on Structure–Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles

“…Semipeptidic macrocycles display a variety of biological activities, such as antibacterial, antifungal, anticancer, and antiviral activity. 4 Moreover, peptide macrocyclization is a well-established tool to modulate binding affinity, 5 selectivity, 6 signaling profile, 7,8 and PK-ADME properties 9,10 of pharmacologically relevant peptidic ligands. Some synthetic macrocycles have even been used to target previously thought "undruggable" protein−protein interactions 11,12 as these peptides are often considered to fit in a chemical space in-between the biologics and small molecules.…”

“…Macrocycles are attractive scaffolds in drug discovery. − In nature, they often occur as macrocycles of peptides and nonpeptidic complex molecules. Semipeptidic macrocycles display a variety of biological activities, such as antibacterial, antifungal, anticancer, and antiviral activity . Moreover, peptide macrocyclization is a well-established tool to modulate binding affinity, selectivity, signaling profile, , and PK-ADME properties , of pharmacologically relevant peptidic ligands.…”