Chemical biology articles within Nature Chemistry

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  • Article |

    Current photodynamic therapy photosensitizers require oxygen; however, tumours are often hypoxic. Now, an organoiridium complex with an unusually high redox potential, which is effective in normoxia and hypoxia, has been developed. The organoiridium complex kills cancer cells by an immunogenic apoptotic mechanism involving efficient photocatalytic oxidation of NADH to NAD radicals, and reduction of cytochrome c.

    • Huaiyi Huang
    • , Samya Banerjee
    •  & Peter J. Sadler

  • Article |

    The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

    • Qingyun Dan
    • , Sean A. Newmister
    •  & Robert M. Williams

  • Article |

    Colibactin is produced by human enterobacteria and assumed to be a gut bacterial genotoxin. Now, colibactin-645 has been identified as a macrocyclic colibactin metabolite that contains a C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety and induces DNA double-strand breaks in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism.

    • Zhong-Rui Li
    • , Jie Li
    •  & Pei-Yuan Qian

  • Article |

    Polytheonamides are potently cytotoxic hypermodified ribosomal peptides that are produced by an uncultivated bacterium. Now, a bioinformatic mining strategy has enabled the development of a bacterial production host that can be cultivated in a laboratory. The host generates polytheonamide-like compounds within 2 days, and can efficiently introduce multiple d-amino acids, asparagine N-methylations and C-methyl groups into various peptides.

    • Agneya Bhushan
    • , Peter J. Egli
    •  & Jörn Piel

  • Review Article |

    ortho-Aminomethylphenylboronic acids are routinely used in sensors for carbohydrates, but the function of the o-aminomethyl group in enhancing binding affinity and modulating the emission of appended fluorophores has been the matter of some debate. This Review presents a unified picture of the structural features, mechanisms of sugar complexation and photophysics of these kinds of sensors.

    • Xiaolong Sun
    • , Brette M. Chapin
    •  & Eric V. Anslyn

  • Article |

    High concentrations of prebiotic molecules and dry–wet cycles are difficult to achieve in a submerged system. Now, it has been shown that temperature gradients across gas bubbles in submerged rock pores can provide these conditions. Molecules are continuously accumulated at the warm side of bubbles at the gas–water interface, which enables or enhances many prebiotically relevant processes.

    • Matthias Morasch
    • , Jonathan Liu
    •  & Dieter Braun

  • Article |

    LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

    • Yujuan Cai
    • , Yang Hai
    •  & Yi Tang

  • Article |

    A method for engineering chemically modified proteins has now been developed using a chemoenzymatic cascade of sortase-mediated transpeptidation and protein trans-splicing. Using this one-pot approach enabled the generation of site-specifically modified proteins in vitro and in isolated cell nuclei.

    • Robert E. Thompson
    • , Adam J. Stevens
    •  & Tom. W. Muir

  • News & Views |

    Nature harnesses fractal geometry to create structures with unusual surface-to-volume ratios. Now, a new design approach enables the reversible assembly of functional enzymes into arboreal patterns with fractal geometry.

    • Iris D. Young
    •  & James S. Fraser

  • Article |

    Abasic sites are amongst the most common forms of DNA damage. Despite their biological significance, little is known regarding the distribution of these sites within DNA. Now a method to sequence abasic sites at single-nucleotide resolution has been developed. This method allows the location of abasic sites to be mapped genome-wide.

    • Zheng J. Liu
    • , Sergio Martínez Cuesta
    •  & Shankar Balasubramanian

  • Article |

    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.

    • Mickal Nawatha
    • , Joseph M. Rogers
    •  & Ashraf Brik

  • Article |

    Non-ribosomal peptide synthetases have now been modified and de novo non-ribosomal peptide synthetases constructed using new assembly points within condensation domains. This approach enabled the production of new-to-nature peptides, including some carrying synthetic amino acids, as well as the generation of peptide libraries.

    • Kenan A. J. Bozhüyük
    • , Annabell Linck
    •  & Helge B. Bode

  • News & Views |

    The longstanding ‘polyelectrolyte theory of the gene’ proposes that a multiply charged backbone is the universal signature of all genetic polymer systems that support life. Now, the first tenable challenge to this theory has been mounted, through the successful engineering of enzymes which can synthesize and reverse-transcribe from an artificial, uncharged nucleic acid analogue.

    • Asha Brown
    •  & Tom Brown

  • News & Views |

    Methods for generating molecular diversity provide a route to screen a wider section of chemical space, to discover compounds with useful biological properties. Now, a complexity-to-diversity strategy has enabled the discovery of a multi-cyclic structure from a complex natural product that induces ferroptotic cell death in cancer cells.

    • Tatiana Cañeque
    •  & Raphaël Rodriguez

  • Article |

    A set of stereochemically complex and structurally diverse compounds were created from the diterpene natural product pleuromutilin using the complexity-to-diversity strategy. Phenotypic screening identified a compound that induces rapid ferroptotic death of cancer cells. Experiments to probe the mechanism revealed the compound to be an inhibitor of thioredoxin.

    • Evijola Llabani
    • , Robert W. Hicklin
    •  & Paul J. Hergenrother

  • News & Views |

    Bacterial communication is a potential strategy to control bacterial behaviours and thus, attenuate pathogen infectivity; however, identifying the signalling molecules that regulate communication pathways is challenging. Now, a robust strategy to rapidly identify previously unknown signalling peptides has been developed. This approach provides a means to map out and decipher bacterial signalling mechanisms.

    • Dominic N. McBrayer
    •  & Yftah Tal-Gan

  • Article |

    The highly charged phosphodiester chemistry of the natural nucleic acids DNA and RNA has been widely considered to be indispensable for their function as informational molecules. Now, synthetic genetic polymers with an uncharged alkyl phosphonate backbone chemistry have been shown to enable genetic information transfer and evolution.

    • Sebastian Arangundy-Franklin
    • , Alexander I. Taylor
    •  & Philipp Holliger

  • Review Article |

    Biochemical and cellular assays are often plagued by false positive readouts elicited by nuisance compounds. A significant proportion of those compounds are aggregators. This Review discusses the basis for colloidal aggregation, experimental methods for detecting aggregates and analyses recent progress in computer-based systems for detecting colloidal aggregation with particular emphasis on machine learning [In the online version of this Review originally published, the graphical abstract image was incorrectly credited to ‘Reven T.C. Wurman / Alamy Stock Photo’ this has now been corrected].

    • Daniel Reker
    • , Gonçalo J. L. Bernardes
    •  & Tiago Rodrigues

  • Article |

    A strategy for directly synthesizing unnatural polymers in cells through radical polymerization has now been developed. This approach provides a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules and a variety of nanostructures.

    • Jin Geng
    • , Weishuo Li
    •  & Mark Bradley

  • Article |

    Two chemical probes, YnF and YnGG, that enable the identification of prenylated peptides and global analysis of protein prenylation using quantitative chemical proteomics have now been developed. Prenylation dynamics in response to pharmacological inhibition of prenyl-transferase enzymes were also studied. As a final demonstration, defective Rab prenylation in a model of the retinal degenerative disease choroideremia was also quantified.

    • Elisabeth M. Storck
    • , Julia Morales-Sanfrutos
    •  & Edward W. Tate

  • Article |

    RNA is usually considered to be the first genetic polymer, with DNA a product of a biochemical pathway that arose after the origin of life. Now, studies into the prebiotic phosphorylation of an RNA nucleoside reveal pathways for the synthesis of DNA building blocks, providing experimental support for a prebiotic link between RNA and DNA.

    • Jianfeng Xu
    • , Nicholas J. Green
    •  & John D. Sutherland

  • News & Views |

    Natural products often provide lead scaffolds for the development of therapeutics, but complexity of their synthesis can limit the discovery of improved analogues. Pharmacophore-directed retrosynthesis aims to accelerate the building of a structure–activity relationship profile of a natural product, aiming to identifying a simplified lead.

    • Jason R. Hudlicky
    •  & Gary A. Sulikowski

  • News & Views |

    Maleimide–thiol adducts are popular in both bioconjugation and materials chemistry, however, they are unstable under physiological conditions. Now, a mechanochemical approach uses pulling forces to stabilize maleimide–thiol adducts and improve the stability of polymer–protein conjugates.

    • Cody J. Higginson
    •  & Phillip B. Messersmith

  • Article |

    Pharmacophore-directed retrosynthesis targets a potential pharmacophore from early on in a natural product synthesis and incremental increases in the complexity of this minimal structure enable a SAR profile to develop over the course of the campaign. The method is applied to gracilin A, finding simplified derivatives displaying potent immunosuppressive effects or selective neuroprotective effects in cell-based assays.

    • Mikail E. Abbasov
    • , Rebeca Alvariño
    •  & Daniel Romo

  • Article |

    Biosynthesis of peptidoglycan requires carefully orchestrated transpeptidation reactions to maintain the structural integrity of this essential component of the bacterial cell wall. Now, rotor-fluorescent d-amino acids have been shown to enable real-time tracking of these transpeptidation reactions in live bacterial cells. These powerful tools allow visualization of peptidoglycan biosynthesis with high spatiotemporal resolution.

    • Yen-Pang Hsu
    • , Edward Hall
    •  & Michael S. VanNieuwenhze

  • News & Views |

    Enzymatic approaches to synthesize oligosaccharides offer an alternative to chemical syntheses for the production of homogeneous glycans; however, enzyme-based routes typically require lengthy processes. Now, the design of a water-soluble affinity tag has enabled the automation of multistep enzymatic syntheses of mammalian oligosaccharides.

    • Nicola L. B. Pohl

  • Article |

    An automated platform that can synthesize a wide range of complex glycans could greatly facilitate progress in glycoscience. Now, a fully automated process for enzyme-mediated oligosaccharide synthesis has been developed. This process uses glycosyltransferase-catalysed reactions performed in solution, with product purification being accomplished by solid phase extraction using a sulfonate tag.

    • Tiehai Li
    • , Lin Liu
    •  & Geert-Jan Boons

  • Article |

    A concise strategy for engineering functional, supramolecular protein complexes has now been developed based on single-mutation-mediated covalent tethering. Metalloproteins designed with this method can sustain large alterations to the metal coordination environment, bind small molecules, exhibit reversible redox activity and sustain large alterations to the protein structure.

    • Jonathan Rittle
    • , Mackenzie J. Field
    •  & F. Akif Tezcan

  • News & Views |

    One goal of synthetic biologists is to develop artificial systems to help study biological processes. Now, cell communication and differentiation have been demonstrated using spatiotemporal patterns created in artificial multicellular compartments.

    • Yi Li
    •  & Rebecca Schulman

  • Article |

    Rapamycin and FK506 are macrocycles that contain an FKBP-binding domain and an effector domain responsible for interacting with their respective targets, mTOR and calcineurin. Now, a 45,000-compound macrocycle library has been synthesized by fusing oligopeptides with synthetic FKBP-binding domains. Screening and subsequent optimization yielded a highly potent FKBP-dependent inhibitor of hENT1.

    • Zufeng Guo
    • , Sam Y. Hong
    •  & Jun O. Liu

  • Article |

    Preparation of well-defined N-glycans is very demanding, which hampers progress in glycoscience. Now, a biomimetic synthetic approach has been developed in which a readily available bi-antennary glycan can be converted in ten or fewer steps into multi-antennary N-glycans. This approach enables each arm to be uniquely extended by glycosyltransferases to give complex branched N-glycans.

    • Lin Liu
    • , Anthony R. Prudden
    •  & Geert-Jan Boons

  • Article |

    Synthetic gene circuits encapsulated in lipid membrane compartments are often employed as artificial cell mimics, but these lack the complex behaviour of biological tissues. Now, spatial information based on chemical gradients has been used to engineer non-trivial dynamics such as signal propagation and differentiation in an artificial multicellular system.

    • Aurore Dupin
    •  & Friedrich C. Simmel

  • Article |

    Synthetic receptors can be used to help understand biological systems, but rarely compete in terms of affinity or selectivity. Now, a glucose-binding compound has been prepared that, despite its symmetry and simplicity, can match all but the strongest glucose-binding proteins. The high binding affinity and outstanding selectivity of this receptor may translate into biomedical applications.

    • Robert A. Tromans
    • , Tom S. Carter
    •  & Anthony P. Davis

  • Article |

    The preparation of conjugates between proteins and small molecules is often challenging and requires several synthetic steps to functionalize each component for conjugation. Now, a conjugation methodology that leverages an electrophilic Se–S bond of selenocysteine to create bioconjugates between polypeptides and complex small molecules has been described.

    • Daniel T. Cohen
    • , Chi Zhang
    •  & Bradley L. Pentelute

  • Thesis |

    Bruce Gibb focuses on fatty acids and wonders whether we’ll all be eating cyanobacteria before too long.

    • Bruce C. Gibb

  • Article |

    A chemical proteomic strategy has now been developed for profiling pyridoxal-phosphate dependent enzymes (PLP-DEs) in cells. Pyridoxal-based probes are phosphorylated in situ and bind to cellular PLP-DEs as cofactor mimics. The method accessed 73% of the Staphylococcus aureus PLP-dependent proteome and annotated uncharacterized proteins as novel PLP-DEs.

    • Annabelle Hoegl
    • , Matthew B. Nodwell
    •  & Stephan A. Sieber

  • Article |

    New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.

    • George Karageorgis
    • , Elena S. Reckzeh
    •  & Herbert Waldmann

  • Article |

    Lipid membranes—which separate cells and organelles from their environment—experience tension during various cell processes; however, measuring membrane tension is notoriously difficult. Now, a new fluorescent, mechanosensitive membrane probe called FliptR has been developed. FliptR enables simple, direct membrane tension measurements in cellular and artificial membranes.

    • Adai Colom
    • , Emmanuel Derivery
    •  & Aurélien Roux

  • Article |

    Natural product chemistry remains critical to the discovery of small molecules that possess unique bioactivities. A collaborative approach to studying the phomactin diterpenoid family that spans isolation, chemical synthesis and investigation of their bioactivity is now reported. The novel congeners that were isolated inspired a divergent strategy to achieve their practical preparation and their anti-tumour evaluation.

    • Yusuke Kuroda
    • , Karen J. Nicacio
    •  & Richmond Sarpong

  • News & Views |

    A new pyrrolysyl-tRNA synthetase/PyltRNA (PylRS/PyltRNA) pair that is mutually orthogonal to existing PylRS/PyltRNA pairs has now been discovered and optimized. This system could enable the site-specific incorporation of a greater number of distinct non-canonical amino acids into a protein.

    • William S. C. Ngai
    •  & Peng R. Chen

  • Article |

    Molecular dynamics simulations for seven members of the Src kinase family have now revealed a conserved step-wise deactivation process, potentially druggable intermediate states, and quantitatively similar thermodynamics and kinetics across the entire family.

    • Mohammad M. Sultan
    • , Gert Kiss
    •  & Vijay S. Pande

  • Editorial |

    Encoded chemical libraries can be used to screen a vast array of compounds against a protein target to identify potent binders. A collection of articles in this issue discuss different methods to increase the chemical space sampled by encoded macrocycle libraries and the advantages that such libraries offer for discovering new drug leads.

  • Q&A |

    Ghotas Evindar, Chemistry Group Leader at GlaxoSmithKline, talks with Nature Chemistry about the advantages of using encoded libraries in drug discovery and the challenges these technologies present.

    • Russell Johnson

  • News & Views |

    Certain drug targets have been deemed undruggable because of the difficulty in finding pharmacologically useful inhibitors. Now, two teams have developed exciting technologies for the creation of diverse collections of macrocyclic molecules and have demonstrated their usefulness for discovering macrocyclic inhibitors.

    • Emil S. Iqbal
    •  & Matthew C. T. Hartman

  • Article |

    The [4Fe4S]2+ cluster-containing DNA-repair enzyme MUTYH helps safeguard the integrity of Watson–Crick base pairing and the human genetic code. The MUTYH [4Fe4S]2+ cluster mediates DNA redox signalling and DNA lesion identification. Now, a MUTYH pathologic variant associated with catastrophic [4Fe4S]2+ cluster redox degradation, impairment of DNA signalling and human colonic tumorigenesis has been identified.

    • Kevin J. McDonnell
    • , Joseph A. Chemler
    •  & Stephen B. Gruber

  • Article |

    Pyrrolysyl-tRNA synthetase(PylRS)/PyltRNACUA pairs that lack the N-terminal domain but are active and orthogonal are discovered, and pairs that are mutually orthogonal to existing PylRS/PyltRNACUA pairs are developed. Mutually orthogonal PylRS/PyltRNA pairs are combined to genetically encode the incorporation of distinct ncAAs into proteins synthesized in E. coli.

    • Julian C. W. Willis
    •  & Jason W. Chin

  • Article |

    An effective antiviral against the common cold could prevent exacerbations in asthma and chronic obstructive pulmonary disease, but the diversity and adaptability of the virus makes it a highly challenging target. Now, picomolar inhibitors of a human lipid transferase have been developed. Targeting this human lipid transferase could provide an effective and broad-spectrum approach to block viral replication in the host.

    • Aurélie Mousnier
    • , Andrew S. Bell
    •  & Edward W. Tate

  • Article |

    A new concept for targeted drug delivery based on enrichment triggered prodrug activation has been developed. Without enrichment, the activation reaction is sluggish; however, following enrichment, the increased concentration enhances the activation reaction rate, thereby leading to the release of the payload. The same approach can be used in antibody–drug conjugate applications.

    • Yueqin Zheng
    • , Xingyue Ji
    •  & Binghe Wang

  • Article |

    Cholesterol embedded in lipid membranes strongly promotes the aggregation of Aβ42 that is associated with Alzheimer's disease. Now, a kinetic analysis has shown that the mechanism of action responsible for this effect involves the introduction of a heterogeneous nucleation pathway that enhances the primary nucleation rate of Aβ42 aggregation by up to 20-fold.

    • Johnny Habchi
    • , Sean Chia
    •  & Michele Vendruscolo

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