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In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ^2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (M^pro). A co-crystal structure revealed the contribution of this cγAA to M^pro binding and the proteolytic stability of these macrocycles.

Peripheral blood mononuclear cells from 73 Japanese patients with coronavirus disease 2019 (COVID-19) and 75 healthy controls were analyzed using single-cell transcriptomics. Combining these data with genotyping data highlights the interplay between host genetics and the immune response in modulating disease severity.

Despite recent advances in engineering of in vitro translation systems, direct ribosomal incorporation of hydroxyhydrocarbon moieties—which can endow peptides with unique biochemical/folding properties—remains challenging. Now, incorporation of translation-compatible azide/hydroxy acids and their post-translational tandem backbone-acyl shifts have enabled in vitro ribosomal synthesis of peptides containing various hydroxyhydrocarbon units.

His-C2-directed modification is chemically challenging and rarely occurs in nature due to the low reactivity of this position. Now, the prenlytransferase LimF has been discovered and applied for geranylation of histidine-containing peptides and imidazole-containing small molecules, showcasing the versatility of this biocatalyst.

RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.

Finding a selective modulator of Lys63-linked ubiquitin chains has proven very challenging. Here, the authors develop potent macrocyclic peptide binders of Lys63-linked di-ubiquitin chains that interrupt DNA damage repair and lead to apoptotic cell death.

Azoles are five-membered heterocycles found in peptidic natural products and synthetic peptiodomimetics. Here the authors demonstrate a posttranslational chemical modification method for in vitro ribosomal synthesis of peptides with exotic azole groups at specific positions.

Lactazole A is a thiopeptide from Streptomyces lactacystinaeus, encoded by a compact 9.8 kb biosynthetic gene cluster. Here, the authors show a platform for in vitro biosynthesis of lactazole A via a combination of a flexible in vitro translation system with recombinantly produced lactazole biosynthetic enzymes.

The development of small volume chamber arrays has greatly facilitated high throughput biological assays of soluble proteins. Here, Watanabe et al.adapt this approach to develop an arrayed lipid bilayer chamber system for single molecule level measurements of membrane transporter activity.

River blindness, a disease affecting millions throughout the tropics, is caused by parasitic worms. Here, Yuet al. report the discovery and structural characterization of potent macrocyclic peptide inhibitors of iPGM, a nematode-specific phosphoglycerate mutase, as potential leads for novel antimicrobial agents.

Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.

When faced with hypoxic conditions, Mycobacterium tuberculosis adapts its metabolism to generate intermediates reserved for re-initiation of peptidoglycan biosynthesis that can be used as soon as it is re-exposed to normoxia.

JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—viain vitroselection from a vast library of cyclic peptides—that show selectivity over other KDMs.

Here, the authors report bi-functional, wide tropic macrocycles that bind the influenza viral envelope protein hemagglutinin and inhibit virus infection by blocking adsorption and fusion and show efficacy in preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models.

The repertoire of amino acids available for ribosomal peptide synthesis is limited by the genetic code. Now, a method to reduce the redundancy of codons has been developed based on the artificial division of codon boxes. This method enables non-proteinogenic amino acids to be included in peptides without sacrificing proteinogenic ones.

Discovery of macrocyclic ligands to the 19S regulatory particle protein PSMD2 enables the synthesis of heterobifunctional molecules that demonstrate proof-of-concept, targeted degradation of BRD4 through direct engagement of the 26S proteasome.

Goadsporin is an antibacterial peptide highly customized by multiple post-translational modifying enzymes. Here, the authors dissect its biosynthetic pathway byin vitro reconstitution and use their insights to produce goadsporin analogues in vitro and in vivo.

The authors develop a ribozyme, Tx2.1, that is capable of aminoacylating tRNA with specificity for the anticodon from directed evolution of a T-box riboswitch. Tx2.1 could be used to charge non-natural amino acids in an in vitro translation system.

The direct reductive coupling of alkyl alcohol and aryl halide enables efficient access to valuable compounds, but the asymmetric pattern remains unknown. Here the authors describe the enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohol and aryl bromide in the presence of an NHC activating agent.

Modulating particular ubiquitin chains using binding molecules is challenging given the diversity of chain lengths and linkages found in vivo. Now, tight binding modulators that are specific to K48-linked ubiquitin chains have been found by combining protein synthesis and screening of macrocyclic peptide ligands.

A non-volatile memory device that is based on an aluminium scandium nitride (Al_0.68Sc_0.32N) ferroelectric diode can operate at temperatures of up to 600 °C.

The extent to which peptide synthesis by the ribosome can tolerate the inclusion of non-peptidic components is not clear. Yet such hybrids would expand the range of ribosomally synthesized structures. Now it has been shown that tRNAs acylated by aromatic foldamers can initiate the ribosomal synthesis of non-cyclic and cyclic foldamer–peptide hybrid molecules. The oligo-aryl segments contain folding information that can control peptide conformation in the hybrids.

Ribosomes tend to stall during the translation of consecutive proline residues, which can be rescued by the co-translational factor EF-P. Here the authors identify a structural element of tRNA^Proresponsible for specific recognition by EF-P and stimulation of Pro-Pro peptide bond formation.

Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.

The unique properties of selenium have been exploited in protein science. This Review highlights the recent applications of selenium chemistry in protein chemical synthesis, modification, folding, stabilization, the preparation of therapeutic proteins and more.

This Review highlights recent advances in the synthesis and application of mirror-image proteins. Emphasis is placed on strategies for accessing these biomolecules, their use in protein crystallography, drug discovery and efforts towards the generation of mirror-image life.

The structures of three intermediate states of photosystem II, which is crucial for photosynthesis, have been solved at room temperature, shedding new light on this process.

The transcription factor orthodenticle 2 (Otx2) is implicated in head specification in bilaterian lineages, but it is unclear how. Yasuoka et al.now show that this is achieved by the interaction between Otx2 and the transcription factors Lim1 and goosecoid, which activate and repress target genes, respectively.

Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury following intracerebral haemorrhage. In this Review, the authors consider PHO in a novel framework and highlight the clinical relevance of the condition, both as a therapeutic target and as a surrogate marker for novel interventions that target secondary injury.

Zucchini has been identified as an endoribonuclease responsible for the maturation of small RNA molecules that protect the genome from the damaging effects of unrestrained expression of mobile elements.