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.

This minireview describes the syntheses, structure‐photophysical properties relationship, and bioimaging applications of fluorescent coumarins, xanthenes, BODIPYs, and cyanines. Advantages and disadvantages of the emissive units are also discussed, as are general practical issues that need to be considered when using fluorophores in a biological setting.

Despite the availability of numerous antiepileptic drugs, 20–30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.

The development of more active CH oxidation catalysts has inspired a rapid, scalable, and stereoselective assembly of multifunctional piperazines through a [3+3] coupling of azomethine ylides. A combination of visible‐light irradiation and aluminum organometallics is essential to promote this transformation, which introduces visible‐light photochemistry of main‐group organometallics and sets the basis for new and promising catalysts.

In this study, we present a series of solvatochromic phenylbenzothiadiazoles that display dual emission from the locally excited (LE) and intramolecular charge transfer (ICT) excited states. The donor‐acceptor derivatives are highly sensitive to polarity changes, which can be monitored by differences in emission efficiency, spectroscopic shifts and variations of the LE/ICT ratio. One of the compounds in the series, containing a thiomethyl substituent, emerged as an excellent blue emitting stain for intracellular lipid droplets, a biomarker for various types of cancer. In addition, a non‐emissive nitro derivative becomes fluorescent upon bioreduction in hypoxic cancer cells and accumulates in lipid droplets with a high signal‐to‐background ratio.

Protein engineering techniques have vastly expanded their domain of impact, notably following the success of antibodies. Likewise, smaller peptide therapeutics have carved an increasingly significant niche for themselves in the pharmaceutical landscape. The concept of grafting such peptides onto larger protein scaffolds, thus harvesting the advantages of both, has given rise to a variety of protein engineering strategies that are reviewed herein. We also describe our own “Lasso‐Grafting” approach, which combines traditional grafting concepts with mRNA display to streamline the production of multiple grafted drug candidates for virtually any target.