Articles in 2023

Peptide epimerization is a common but enigmatic post-translational modification found in antibiotics formed from ribosomally synthesized and post-translationally modified peptides. Now, crystallographic snapshots, spectroscopy and biochemical investigations have provided insight into the mechanism of peptide epimerization catalyzed by radical S-adenosyl-l-methionine epimerases.

Cyclic peptides can bind challenging disease targets, but their oral application is hindered by digestion and absorption issues. We developed a versatile method for the synthesis and functional screening of vast numbers of synthetic cyclic peptides and identified peptides with high inhibitory activity, stability and oral bioavailability in rats.

Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

Hiroaki Suga’s research has made substantial contributions to the development of artificial ribozymes and their application in mRNA display libraries. In 2006, Professor Suga help found the biopharmaceutical company PeptiDream Inc. He spoke to Nature Chemical Biology about the future of mRNA display libraries and the advantages they offer.

The requirement for a protospacer adjacent motif (PAM) is a well-known limitation of the CRISPR–Cas9 system, as it restricts the range of sequences that can be targeted. To address this limitation, we demonstrate a phage-assisted evolution approach for engineering a compact SlugCas9, simplifying its PAM requirement and broadening its DNA targeting scope.

Cyclic tetrapeptides (CTPs) have great potential for materials and therapeutics; however, synthesizing these molecules remains a significant challenge. Now, an enzyme has been developed that enables efficient N-to-C cyclization of linear tetrapeptidyl substrates to form structurally diverse CTPs.

Analyzing glycans is challenging because of their structural diversity and complexity and the lack of analytical techniques capable of resolving pools of similar glycan structures. A new method now enables imaging of single glycans, providing direct observation of individual glycans and glycoconjugates.

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

Qi et al. used phage-assisted evolution to optimize SlugCas9, a compact Cas9 nuclease, for NNG PAM recognition and developed a SlugCas9-NNG based adenine base editor for single AAV delivery.

Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

A workflow integrating tools from bioinformatics, structural biology and synthetic biology has been developed that enables the rapid design of pili-enabled living materials. This approach allows mining of pili-producing nonpathogenic chassis, understanding of the pili structure and assembly, and engineering of pili-enabled living materials in a systematic and sequential manner.

Efforts to rationally engineer nonribosomal peptide synthetase (NRPS) enzymes have focused on making individual modifications. Here the authors describe a targeted random engineering approach that uses thousands of NRPS domains amplified from the soil metagenome for mass substitution experiments.