Nicholas J. Mitchell

Peptide‐based vaccines, formulated with an appropriate adjuvant, offer a versatile platform for targeted cancer immunotherapy. While adjuvants are usually coadministered for nucleic acid and protein vaccines, synthetic peptide antigens afford a more effective opportunity to covalently and regioselectively graft immunostimulatory motifs directly onto the antigen scaffold to yield self‐adjuvanting vaccines. Herein, we explore the synthesis of two tissue‐restricted cancer‐testis antigens (CTAs); New York oesophageal cell carcinoma 1 (NY‐ESO‐1) and B melanoma antigen 4 (BAGE4), both carrying the toll‐like receptor (TLR) agonist, Pam₂Cys. These constructs were evaluated in vivo along with a lipid nanoparticle (LNP) preparation of the underexplored BAGE4 melanoma antigen.

An improved method for the synthesis of noncanonical cyclopropane amino acids from common laboratory reagents is described, avoiding the use of neurotoxic oxidants or precious metal catalysts. Intramolecular isocyanate trapping via a Hofmann rearrangement permits the synthesis of bicyclic carbamates in an enantioenriched and diastereopure manner. Subsequent ring-opening of these species allows access to cyclopropane amino acids which can be further functionalized via oxidation and S_N2 pathways and incorporated into peptides via solid-phase peptide synthesis.

Correction for ‘Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation’ by Frances R. Smith et al., Chem. Sci., 2024, 15, 9612–9619, https://doi.org/10.1039/D3SC05865D.

Herein, we report a peptide cyclisation strategy via intramolecular interception of cysteine desulfurisation. This method enables the cyclisation of unprotected peptides in aqueous solution via the installation of a hydrocarbon linkage.

Synthetic methods that enable the macrocyclisation of peptides facilitate the development of more effective therapeutic and diagnostic tools. Herein we report a peptide cyclisation strategy based on intramolecular interception of visible-light-mediated cysteine desulfurisation. This method allows cyclisation of unprotected peptides in an aqueous solution via the installation of a hydrocarbon linkage. We explore the limits of this chemistry using a range of model peptides of increasing length and complexity, including peptides of biological/therapeutic relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin, with a proteolytically/redox-stable hydrocarbon, and internal macrocyclisation of an MCL-1-binding peptide.

‘Bacterial‐type’ ferredoxins host a cubane [4Fe4S]^2+/+ cluster that enables these proteins to mediate electron transfer and facilitate a broad range of biological processes. Peptide maquettes based on the conserved cluster‐forming motif have previously been reported and used to model the ferredoxins. Herein we explore the integration of a [4Fe4S]‐peptide maquette into a H₂‐powered electron transport chain. While routinely formed under anaerobic conditions, we illustrate by electron paramagnetic resonance (EPR) analysis that these maquettes can be reconstituted under aerobic conditions by using photoactivated NADH to reduce the cluster at 240 K. Attempts to tune the redox properties of the iron‐sulfur cluster by introducing an Fe‐coordinating selenocysteine residue were also explored. To demonstrate the integration of these artificial metalloproteins into a semi‐synthetic electron transport chain, we utilize a ferredoxin‐inspired [4Fe4S]‐peptide maquette as the redox partner in the hydrogenase‐mediated oxidation of H₂.

Across eukaryotic proteomes, tryptophan is the least abundant of the 20 canonical amino acids, which makes it an ideal chemical handle for the late-stage functionalization of peptide and protein scaffolds with minimal production of undesired isoforms. Herein, we report the photocatalytic C2-alkylation of tryptophan using bromodifluoroacetate/acetamide-derived radical precursors. This rapid visible-light-mediated reaction is additive-free, operationally simple, and tolerates diverse functionality. We demonstrate the late-stage modification of a variety of complex peptides, including examples of biological significance.

Herein, we report the synthesis and characterization of a new class of hybrid Wells–Dawson polyoxometalate (POM) containing a diphosphoryl group (P₂O₆X) of the general formula [P₂W₁₇O₅₇(P₂O₆X)]⁶⁻(X=O, NH, or CR¹R²). Modifying the bridging unit X was found to impact the redox potentials of the POM. The ease with which a range of α‐functionalized diphosphonic acids (X=CR¹R²) can be prepared provides possibilities to access diverse functionalized hybrid POMs. Compared to existing phosphonate hybrid Wells–Dawson POMs, diphosphoryl‐substituted POMs offer a wider tunable redox window and enhanced hydrolytic stability. This study provides a basis for the rational design and synthesis of next‐generation hybrid Wells–Dawson POMs.

Herein, we report the synthesis and characterization of a new class of hybrid Wells–Dawson polyoxometalate (POM) containing a diphosphoryl group (P₂O₆X) of the general formula [P₂W₁₇O₅₇(P₂O₆X)]⁶⁻(X=O, NH, or CR¹R²). Modifying the bridging unit X was found to impact the redox potentials of the POM. The ease with which a range of α‐functionalized diphosphonic acids (X=CR¹R²) can be prepared provides possibilities to access diverse functionalized hybrid POMs. Compared to existing phosphonate hybrid Wells–Dawson POMs, diphosphoryl‐substituted POMs offer a wider tunable redox window and enhanced hydrolytic stability. This study provides a basis for the rational design and synthesis of next‐generation hybrid Wells–Dawson POMs.

The site‐selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp³)−C(sp³) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible‐light‐mediated reaction is described that enables the site‐selective modification of peptides and proteins via desulfurative C(sp³)−C(sp³) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM‐mimic is successfully integrated into a recombinantly expressed histone.