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Technological advances and breakthrough developments in the pharmaceutical field are knocking at the door of the "undruggable" fortress with increasing insistence. Notably, the 21st century has seen the emergence of macrocyclic compounds, among which cyclic peptides are of particular interest. This new class of potential drug candidates occupies the vast chemical space between classic small-molecule drugs and larger protein-based therapeutics, such as antibodies. As research advances toward clinical targets that have long been considered inaccessible, macrocyclic peptides are well-suited to tackle these challenges in a post-rule of 5 pharmaceutical landscape. Facilitating their discovery is an arsenal of high-throughput screening methods that exploit massive randomized libraries of genetically encoded compounds. These techniques benefit from the incorporation of non-natural moieties, such as non- proteinogenic amino acids or stabilizing hydrocarbon staples. Exploiting these features for the strategic architectural design of macrocyclic peptides has the potential to tackle challenging targets such as protein–protein interactions, which have long resisted research efforts. This Review summarizes the basic principles and recent developments of the main high-throughput techniques for the discovery of macrocyclic peptides and focuses on their specific deployment for targeting undruggable space. A particular focus is placed on the development of new design guidelines and principles for the cyclization and structural stabilization of cyclic peptides and the resulting success stories achieved against well-known inaccessible drug targets. [ABSTRACT FROM AUTHOR]

A series of aromatic oligoamide foldamer sequences containing different proportions of three δ‐amino acids derived from quinoline, pyridine, and benzene and possessing varying flexibility, for example due to methylene bridges, were synthesized. Crystallographic structures of two key sequences and 1H NMR data in water concur to show that a canonical aromatic helix fold prevails in almost all cases and that helix stability critically depends on the ratio between rigid and flexible units. Notwithstanding subtle variations of curvature, i. e. the numbers of units per turn, the aromatic δ‐peptide helix is therefore shown to be general and tolerant of a great number of sp3 centers. We also demonstrate canonical helical folding upon alternating two monomers that do not promote folding when taken separately: folding occurs with two methylenes between every other unit, not with one methylene between every unit. These findings highlight that a fine‐tuning of helix handedness inversion kinetics, curvature, and side chain positioning in aromatic δ‐peptidic foldamers can be realized by systematically combining different yet compatible δ‐amino acids. [ABSTRACT FROM AUTHOR]

Tight binding was observed between the C‐terminal cross section of aromatic oligoamide helices in aqueous solution, leading to the formation of discrete head‐to‐head dimers in slow exchange on the NMR timescale with the corresponding monomers. The nature and structure of the dimers was evidenced by 2D NOESY and DOSY spectroscopy, mass spectrometry and X‐ray crystallography. The binding interface involves a large hydrophobic aromatic surface and hydrogen bonding. Dimerization requires that helices have the same handedness and the presence of a C‐terminal carboxy function. The protonation state of the carboxy group plays a crucial role, resulting in pH dependence of the association. Dimerization is also influenced by neighboring side chains and can be programmed to selectively produce heteromeric aggregates. [ABSTRACT FROM AUTHOR]

Eine starke Bindung wurde zwischen den C‐terminalen Querschnitten von aromatischen Oligoamid‐Helices in wässriger Lösung beobachtet. Diese führt zur Bildung von diskreten Kopf‐an‐Kopf‐Dimeren, die im langsamen Austausch mit den entsprechenden Monomeren auf der NMR‐Zeitskala stehen. Die Art und Struktur der Dimere wurde durch 2D‐NOESY‐ und DOSY‐Spektroskopie, Massenspektrometrie und Röntgenkristallographie nachgewiesen. An der Bindungsschnittstelle beteiligt sind eine große hydrophobe aromatische Oberfläche und Wasserstoffbrückenbindungen. Die Dimerisierung setzt voraus, dass die Helices die gleiche Händigkeit aufweisen und eine C‐terminale Carboxyfunktion vorhanden ist. Der Protonierungszustand der Carboxygruppe spielt eine entscheidende Rolle und führt zu einer pH‐Abhängigkeit der Assoziation. Die Dimerisierung wird auch durch benachbarte Seitenketten beeinflusst und kann programmiert werden, um selektiv heteromere Aggregate zu bilden. [ABSTRACT FROM AUTHOR]

A novel chiral aromatic δ-amino acid building block was shown to fully induce handedness in quinoline oligoamide foldamers with the possibility of further increasing the bias by combining multiples of these units in the same sequence. Through its incorporation within the helix, both N- and C-termini are still accessible for further functionalisation. [ABSTRACT FROM AUTHOR]