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We describe a versatile and tuneable thiol responsive linker system using thiovinylketones, which relies on the conjugate addition–elimination mechanism of Michael acceptors for the traceless release of therapeutics. In a proof-of-principle study, we translate our findings to exhibit potent thiol-cleavable antibiotic prodrugs and antibody–drug conjugates. [ABSTRACT FROM AUTHOR]

CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2. [ABSTRACT FROM AUTHOR]

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method. [ABSTRACT FROM AUTHOR]

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload‐release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide‐containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA‐approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method. [ABSTRACT FROM AUTHOR]

Herein we introduce 3-vinyl-1,2,4-triazines derivatives as dual-reactive linkers that exhibit selectivity towards cysteine and specific strained alkynes, enabling conjugate addition and inverse electron-demand Diels–Alder (IEDDA) reactions. This approach facilitates site-selective bioconjugation of biologically relevant peptides, followed by rapid and highly selective reactions with bicyclononyne (BCN) reagents. [ABSTRACT FROM AUTHOR]

Peptide stapling is a robust strategy for generating enzymatically stable, macrocyclic peptides. The incorporation of biologically relevant tags (such as cell‐penetrating motifs or fluorescent dyes) into peptides, while preserving their binding interactions and enhancing their stability, is highly sought after. Despite the unique opportunities offered by tryptophan's indole scaffold for targeted functionalisation, its utilisation in peptide stapling has been limited as compared to other amino acids. Herein, we present an approach for peptide stapling using the tryptophan‐mediated Petasis reaction. This method enables the synthesis of both stapled and labelled peptides and is applicable to both solution and solid‐phase synthesis. Importantly, the use of the Petasis reaction in combination with tryptophan facilitates the formation of stapled peptides in a straightforward, multicomponent fashion, while circumventing the formation of undesired by‐products. Furthermore, this approach allows for efficient and diverse late‐stage peptide modifications, thereby enabling rapid production of numerous conjugates for biological and medicinal applications. [ABSTRACT FROM AUTHOR]

Peptide stapling is a robust strategy for generating enzymatically stable, macrocyclic peptides. The incorporation of biologically relevant tags (such as cell‐penetrating motifs or fluorescent dyes) into peptides, while preserving their binding interactions and enhancing their stability, is highly sought after. Despite the unique opportunities offered by tryptophan's indole scaffold for targeted functionalisation, its utilisation in peptide stapling has been limited as compared to other amino acids. Herein, we present an approach for peptide stapling using the tryptophan‐mediated Petasis reaction. This method enables the synthesis of both stapled and labelled peptides and is applicable to both solution and solid‐phase synthesis. Importantly, the use of the Petasis reaction in combination with tryptophan facilitates the formation of stapled peptides in a straightforward, multicomponent fashion, while circumventing the formation of undesired by‐products. Furthermore, this approach allows for efficient and diverse late‐stage peptide modifications, thereby enabling rapid production of numerous conjugates for biological and medicinal applications. [ABSTRACT FROM AUTHOR]

Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs are significantly harder to synthesise. Here, we report the synthesis of ADCs loaded with a single warhead, using TetraDVP linkers which simultaneously re-bridge all four interchain disulfides of an IgG1 antibody. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) typically require internalisation into cancer cells to release their cytotoxic payload. However, this places stringent constraints on therapeutic development, requiring cancer targets that have high expression of internalising antigens and efficient intracellular processing. An alternative approach is emerging whereby the payloads can be released extracellularly from cleavable linkers upon binding to poorly-internalising antigens or other tumoral components. This removes the reliance on high antigen expression, avoids potentially inefficient internalisation, and can greatly expand the range of cancer targets to components of the extracellular tumour matrix. This review gives an overview of recent developments towards non-internalising ADCs, including emerging cancer-associated cell surface and extracellular proteins, cancer stromal targeting and the linking chemistry that enables extracellular payload release. [ABSTRACT FROM AUTHOR]

Herein we report the development of a methodology for the dual-functionalisation of IgG antibodies. This is accomplished through the combination of disulfide rebridging divinylpyrimidine technology, with bicyclononyne and methylcyclopropene handles to facilitate sequential SPAAC and IEDDA reactions. Advantageously, the strategy does not require metal catalysis and avoids the need for purification between functionalisation steps. [ABSTRACT FROM AUTHOR]

Herein we report the development of a methodology for the dual-functionalisation of IgG antibodies. This is accomplished through the combination of disulfide rebridging divinylpyrimidine technology, with bicyclononyne and methylcyclopropene handles to facilitate sequential SPAAC and IEDDA reactions. Advantageously, the strategy does not require metal catalysis and avoids the need for purification between functionalisation steps. [ABSTRACT FROM AUTHOR]

In this work, an iterative cycle of enzymatic assays, X-ray crystallography, molecular modelling and cellular assays were used to develop a functionalisable chemical probe for the CK2a/b PPI. The lead peptide, P8C9, successfully binds to CK2a at the PPI site, is easily synthesisable and functionalisable, highly stable in serum and small enough to accommodate further optimisation. [ABSTRACT FROM AUTHOR]

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody–drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours. [ABSTRACT FROM AUTHOR]

The ABC multidrug exporter MsbA mediates the translocation of lipopolysaccharides and phospholipids across the plasma membrane in Gram-negative bacteria. Although MsbA is structurally well characterised, the energetic requirements of lipid transport remain unknown. Here, we report that, similar to the transport of small-molecule antibiotics and cytotoxic agents, the flopping of physiologically relevant long-acyl-chain 1,2-dioleoyl (C18)-phosphatidylethanolamine in proteoliposomes requires the simultaneous input of ATP binding and hydrolysis and the chemical proton gradient as sources of metabolic energy. In contrast, the flopping of the large hexa-acylated (C12-C14) Lipid-A anchor of lipopolysaccharides is only ATP dependent. This study demonstrates that the energetics of lipid transport by MsbA is lipid dependent. As our mutational analyses indicate lipid and drug transport via the central binding chamber in MsbA, the lipid availability in the membrane can affect the drug transport activity and vice versa. Guo et al. conduct a biochemical analysis of the energy dependence of substrate transport by MsbA, an essential ABC lipid transporter in Gram-negative bacteria. The authors examine the flopping of physiologically relevant lipids by MsbA and their differing dependencies on ATP and chemical proton gradient, demonstrating that the energetics of lipid transport by MsbA is lipid dependent. [ABSTRACT FROM AUTHOR]

Bacterial infections caused by 'superbugs' are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chemical synthetic strategies that have been applied to develop novel AMPs, including chemical modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP–drug conjugates and consider recent developments in their chemical synthesis. [ABSTRACT FROM AUTHOR]

Background: Dionysia tapetodes, a small cushion-forming mountainous evergreen in the Primulaceae, possesses a vast surface-covering of long silky fibres forming the characteristic "woolly" farina. This contrasts with some related Primula which instead form a fine powder. Farina is formed by specialized cellular factories, a type of glandular trichome, but the precise composition of the fibres and how it exits the cell is poorly understood. Here, using a combination of cell biology (electron and light microscopy) and analytical chemical techniques, we present the principal chemical components of the wool and its mechanism of exit from the glandular trichome. Results: We show the woolly farina consists of micron-diameter fibres formed from a mixture of flavone and substituted flavone derivatives. This contrasts with the powdery farina, consisting almost entirely of flavone. The woolly farina in D. tapetodes is extruded through specific sites at the surface of the trichome's glandular head cell, characterised by a small complete gap in the plasma membrane, cell wall and cuticle and forming a tight seal between the fibre and hole. The data is consistent with formation and thread elongation occurring from within the cell. Conclusions: Our results suggest the composition of the D. tapetodes farina dictates its formation as wool rather than powder, consistent with a model of thread integrity relying on intermolecular H-bonding. Glandular trichomes produce multiple wool fibres by concentrating and maintaining their extrusion at specific sites at the cell cortex of the head cell. As the wool is extensive across the plant, there may be associated selection pressures attributed to living at high altitudes. [ABSTRACT FROM AUTHOR]

A novel enzyme cleavable linker for antibody–drug conjugates is reported. The 3-O-sulfo-β-galactose linker is cleaved sequentially by two lysosomal enzymes – arylsulfatase A and β-galactosidase – to release the payload in targeted cells. An α-HER2 antibody–drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity. [ABSTRACT FROM AUTHOR]

The growing antimicrobial resistance crisis necessitates the discovery and development of novel classes of antibiotics if a 'postantibiotic era' is to be avoided. Ribosomally synthesised and post-translationally modified peptides, or RiPPs, are becoming increasingly recognised as a potential source of antimicrobial drugs. This is due to a combination of their potent antimicrobial activity and their high stability relative to unmodified linear peptides. However, as peptide drugs, their clinical development is often perturbed by issues such as low solubility and poor bioavailability. Chemical synthesis has the potential to overcome some of these challenges. Furthermore, the structural complexity of RiPPs makes them interesting synthetic targets in their own right, with the total synthesis of some structural classes having only been recently realised. This review focusses on the use of RiPPs as antimicrobial agents and will highlight various strategies that have been employed to chemically synthesise three major classes of RiPPs: lasso peptides, cyclotides, and lanthipeptides. [ABSTRACT FROM AUTHOR]

Peptides can offer the versatility needed for a successful oncology drug discovery approach. Peptide–drug conjugates (PDCs) are an emerging targeted therapeutic that present increased tumour penetration and selectivity. Despite these advantages, there are still limitations for the use of peptides as therapeutics exemplified through their slow progression to get into the clinic and limited oral bioavailability. New approaches to address these problems have been studied and successfully implemented to enhance the stability of peptides and their constructs. There is great promise for the future of PDCs with two molecules already on the market and many variations currently undergoing clinical trials, such as bicycle-toxin conjugates and peptide–dendrimer conjugates. This review summarises the entire process needed for the design and successful development of an oncology PDC including chemical and nanomaterial strategies to enhance peptide stability within circulation, the function of each component of a PDC construct, and current examples in clinical trials. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs. [ABSTRACT FROM AUTHOR]

Amino acid modification plays an important role across several fields, including synthetic organic chemistry, materials science, targeted drug delivery and the probing of biological function. Although a myriad of methods now exist for the modification of peptides or proteins, many of these target a handful of the most reactive proteinogenic amino acids. Photocatalysis has recently emerged as a mild approach for amino acid modification, generating a sizable toolbox of reactions capable of modifying almost all of the canonical amino acids. These reactions are characterised by their mild, physiologically compatible conditions, greatly enhancing their usefulness for amino acid modification. This review aims to introduce the field of photocatalytic amino acid modification and discusses the most recent advances. [ABSTRACT FROM AUTHOR]

Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics. [ABSTRACT FROM AUTHOR]

Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics. [ABSTRACT FROM AUTHOR]

All-syn fused cyclobutanes remain an elusive chemotype and thus present an interesting synthetic challenge. Herein, we report the successful application of Pd-catalysed C(sp3)–H arylation of cyclobutane compounds to generate all-syn heterobicyclic fragments using an innovative 'inside-out' approach. Through this strategy we generate a virtual collection of 90 fragments, which we demonstrate to have enhanced three-dimensionality and superior fragment-like properties compared to existing collections. [ABSTRACT FROM AUTHOR]

Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide. [ABSTRACT FROM AUTHOR]

Herein, we describe the natural product inspired synthesis of 38 complex small molecules based upon 20 unique frameworks suitable for fragment-based screening. Utilising an efficient strategy, two key building block diastereomers were harnessed to generate novel, three-dimensional fragments which each possess numerous synthetically accessible fragment growth positions. [ABSTRACT FROM AUTHOR]

The aplyronines are a family of highly cytotoxic marine natural products with potential application in targeted cancer chemotherapy. To address the severe supply issue, function-oriented molecular editing of their macrolactone scaffold led to the design of a series of simplified aplyronine analogues. Enabled by a highly convergent aldol-based route, the total synthesis of four analogues was achieved, with a significant improvement in step economy versus previous compounds, and their cancer cell growth inhibition in the HeLa cell line was determined. The modular strategy presented offers a means for significantly shortening their chemical synthesis to facilitate the continued development of this promising class of anticancer agent. [ABSTRACT FROM AUTHOR]

N -Substituted dipropargylamines that are suitable as functionalized linkers for peptide stapling can be synthesized in one step under mild conditions from commercially available starting materials (41% to quantitative yield). [ABSTRACT FROM AUTHOR]

In recent years the pharmaceutical industry has benefited from the advances made in fragment‐based drug discovery (FBDD) with more than 30 fragment‐derived drugs currently marketed or progressing through clinical trials. The success of fragment‐based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2‐rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three‐dimensional scaffolds. Herein, we report step‐efficient routes to a number of biologically relevant, fragment‐like heterocyclic spirocycles. The use of both electron‐deficient and electron‐rich 2‐atom donors was explored in complexity‐generating [3+2]‐cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses. [ABSTRACT FROM AUTHOR]

Antibody–Drug Conjugates (ADCs) are now established as a major class of therapeutics for the clinical treatment of cancer. The properties of the linker between the antibody and the payload are proven to be critical to the success of an ADC. Although ADC linkers can be 'non-cleavable', the vast majority of ADCs in clinical development have specific release mechanisms to allow controlled linker cleavage at the target site and are thus termed 'cleavable'. In recent years, the development of new methods of drug release from ADCs has continued in parallel to the deepening understanding of the biological processes underlying the mechanisms of action of pre-existing technologies. This review summarises the advances in the field of cleavable linker technologies for ADCs. [ABSTRACT FROM AUTHOR]

We report a novel divinyltriazine linker for the stapling of two cysteine residues to form macrocyclic peptides from their unprotected linear counterparts. The stapling reaction occurred rapidly under mild conditions on a range of unprotected peptide sequences. The resulting constrained peptides displayed greater stability in a serum stability assay when compared to their linear counterparts. [ABSTRACT FROM AUTHOR]

Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53–MDM2 protein–protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53–MDM2 PPI. [ABSTRACT FROM AUTHOR]