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Glycosylated polyene macrolides are important antifungal agents that are produced by many actinomycete species. Development of new polyenes may deliver improved antibiotics. Here, Streptomyces nodosus was genetically re-programmed to synthesise pentaene analogues of the heptaene amphotericin B. These pentaenes are of interest as surrogate substrates for enzymes catalysing unusual, late-stage biosynthetic modifications. The previous deletion of amphotericin polyketide synthase modules 5 and 6 generated S. nodosus M57, which produces an inactive pentaene. Here, the chain-terminating thioesterase was fused to module 16 to generate strain M57-16TE, in which cycles 5, 6, 17 and 18 are eliminated from the biosynthetic pathway. Another variant of M57 was obtained by replacing modules 15, 16 and 17 with a single 15–17 hybrid module. This gave strain M57-1517, in which cycles 5, 6, 15 and 16 are deleted. M57-16TE and M57-1517 gave reduced pentaene yields. Only M57-1517 delivered its predicted full-length pentaene macrolactone in low amounts. For both mutants, the major pentaenes were intermediates released from modules 10, 11 and 12. Longer pentaene chains were unstable. The novel pentaenes were not glycosylated and were not active against Candida albicans. However, random mutagenesis and screening may yet deliver new antifungal producers from the M57-16TE and M57-1517 strains.

The rational and controlled synthesis of metallo‐organic cages using polyaromatic ligands is well established in the literature. There is a strong interest to advance this field towards the use of chiral ligands capable of yielding cages in a stereoselective manner. Herein, we demonstrate that the classical approach for designing metallo‐organic cages can be translated to polyproline peptides, a biocompatible class of chiral ligands. We have successfully designed a series of polyprolines, which mimic the topology of ditopic polyaromatic ligands, to achieve the stereoselective synthesis of a novel Pd lantern cage. This cage exhibits excellent stability in water and demonstrates the stabilization of a highly reactive species in solution. This work will pave the way towards the stereospecific synthesis of more complex, functionalized peptide‐based metallo‐cages. The design principles used for the synthesis of classical metallo‐organic ligands have been successfully translated to polyproline peptides, a biocompatible class of chiral ligands. These peptide‐based ditopic ligands have been successfully used to stereoselectively synthesize a novel Pd lantern cage, which exhibits excellent stability in water and demonstrates the stabilization of a highly reactive species in solution.

Structural and thermodynamic characterization of the interaction between the intrinsically disordered HBV protein preS1 and the human adaptor protein γ2-EAR indicates that the viral protein imitates host cell interaction motifs to gain access to the cellular trafficking system. Hepatitis B virus (HBV) is an infectious, potentially lethal human pathogen. However, there are no effective therapies for chronic HBV infections. Antiviral development is hampered by the lack of high-resolution structures for essential HBV protein-protein interactions. The interaction between preS1, an HBV surface-protein domain, and its human binding partner, γ2-adaptin, subverts the membrane-trafficking apparatus to mediate virion export. This interaction is a putative drug target. We report here atomic-resolution descriptions of the binding thermodynamics and structural biology of the interaction between preS1 and the EAR domain of γ2-adaptin. NMR, protein engineering, X-ray crystallography and MS showed that preS1 contains multiple γ2-EAR–binding motifs that mimic the membrane-trafficking motifs (and binding modes) of host proteins. These motifs localize together to a relatively rigid, functionally important region of preS1, an intrinsically disordered protein. The preS1–γ2-EAR interaction was relatively weak and efficiently outcompeted by a synthetic peptide. Our data provide the structural road map for developing peptidomimetic antivirals targeting the γ2-EAR–preS1 interaction.

The rise of antifungal resistance threatens public health and agriculture. Iturin A, a cyclic lipopeptide produced by Bacillus species, is known for its antifungal activity against various pathogens. In this study, three novel trifluoromethylated analogues of iturin A were synthesised as potential 19F NMR probes and to compare their bioactivity with the natural compound. Trifluoromethylation targeted the D‐tyrosine and iturinic acid residues, which are critical for antifungal activity. Fluorinated building blocks were prepared via oxidative radical trifluoromethylation for D‐tyrosine and, notably, via electrophilic trifluoromethylation combined with a chiral auxiliary‐based approach for the iturinic acid, marking the first synthesis of a terminally trifluoromethylated long‐chain β‐amino fatty acid. Peptide assembly was achieved through solid‐phase synthesis followed by on‐resin cyclisation, alongside a high‐yielding late‐stage aromatic trifluoromethylation method. Bioactivity assays revealed that the mono‐trifluoromethylated tyrosine analogue exhibited slight activity loss against Candida albicans and greater loss against Fusarium graminearum. The bis‐trifluoromethylated tyrosine analogue lost activity against both fungi, while the alkyl‐trifluoromethylated analogue retained full activity against C. albicans and showed a minor activity loss against F. graminearum. These analogues provide insights into site‐specific trifluoromethylation effects, can serve as valuable 19F NMR probes, and can be a platform for further iturin A analogue development. Iturin A is an antifungal lipopeptide with broad applications. Here, we present a novel synthesis and semisynthesis of trifluoromethylated iturin A analogues. Their antifungal activity was evaluated against Fusarium graminearum and Candida albicans. The lipopeptides are expected to be useful 19F NMR probes for mechanistic studies and the proposed synthesis can enable the development of further iturin A analogues.

The Cover Feature celebrates the stereoselective synthesis of a peptide‐based palladium cage. The chiral, low‐symmetry peptide‐based ligand used to generate this Pd cage could theoretically yield up to four structural isomers. Remarkably, only a single isomeric cage is formed in solution, the thermodynamically stable one. The image represents the single isomer emerging into the spotlight from all the possible isomers, shown in different colours in the background. More information can be found in the Research Article by A. Palma and co‐workers (DOI: 10.1002/ceur.202400050).

The rational and controlled synthesis of metallo‐organic cages using polyaromatic ligands is well established in the literature. There is a strong interest to advance this field towards the use of chiral ligands capable of yielding cages in a stereoselective manner. Herein, we demonstrate that the classical approach for designing metallo‐organic cages can be translated to polyproline peptides, a biocompatible class of chiral ligands. We have successfully designed a series of polyprolines, which mimic the topology of ditopic polyaromatic ligands, to achieve the stereoselective synthesis of a novel Pd lantern cage. This cage exhibits excellent stability in water and demonstrates the stabilization of a highly reactive species in solution. This work will pave the way towards the stereospecific synthesis of more complex, functionalized peptide‐based metallo‐cages.

The rational and controlled synthesis of metallo-organic cages using polyaromatic ligands is well established in the literature. There is a strong interest to advance this field towards the use of chiral ligands capable of yielding cages in a stereoselective manner. Herein, we demonstrate that the classical approach for designing metallo-organic cages can be translated to polyproline peptides, a biocompatible class of chiral ligands. We have successfully designed a series of polyprolines, which mimic the topology of ditopic polyaromatic ligands, to yield the stereoselective synthesis of a novel Pd lantern cage. This work will pave the way towards the stereospecific synthesis of more complex, functionalized peptide cages.