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The development of novel covalent organic polymers (COPs) incorporating nitrone linkages and their chemical transformation into new materials through tandem reactions is reported. Using 1,3,5‐tris(4‐hydroxyaminophenyl)triazine and terephthaldehyde as building blocks, a nitrone‐linked COP was synthesized under mild conditions. The inherent versatility of the nitrone moiety enabled the formation of oxime O‐ether‐linked COPs through simple thermal treatment of the same monomers. Additionally, making use of the well‐known 1,3‐dipolar cycloaddition reaction with nitrones, a multicomponent transformation with phenylvinylsulfone led to the formation of a new isoxazolidine‐linked polymer. Structural and chemical characterizations using FT‐IR, 13C and 15N CP‐MAS NMR, XPS, and scanning electron microsopy (SEM) confirmed the successful formation of the polymeric materials and the direct nitrone conversion into different groups and moieties. These results demonstrate the versatility of nitrone linkages for creating diverse COPs and expand the toolbox for designing functional organic materials. The nitrone moiety's versatility in covalent organic polymer (COP) materials is shown by its ability to form either nitrone‐linked or oxime O‐ether‐linked COPs from the same building blocks, simply by changing reaction conditions. Additionally, its 1,3‐dipolar cycloaddition reactivity enabled the synthesis of a functionalized isoxazolidine‐linked polymer via phenylvinylsulfone addition during polymer formation.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric αβγ complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK’s kinase activity, allowing it to upregulate ATP-generating catabolic pathways and to reduce energy-consuming catabolic pathways and cellular programs. AMPK senses the cellular energy state by competitive binding of the three adenine nucleotides AMP, ADP, and ATP to three sites in its γ subunit, each, which in turn modulates the activity of AMPK’s kinase domain in its α subunit. Our current understanding of adenine nucleotide binding and the mechanisms by which differential adenine nucleotide occupancies activate or inhibit AMPK activity has been largely informed by crystal structures of AMPK in different activity states. Here we provide an overview of AMPK structures, and how these structures, in combination with biochemical, biophysical, and mutational analyses provide insights into the mechanisms of adenine nucleotide binding and AMPK activity modulation.

An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of.

The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.

The phycobilisome (PBS) is an extra-membrane supramolecular complex composed of many chromophore (bilin)-binding proteins (phycobiliproteins) and linker proteins, which generally are colorless. PBS collects light energy of a wide range of wavelengths, funnels it to the central core, and then transfers it to photosystems. Although phycobiliproteins are evolutionarily related to each other, the binding of different bilin pigments ensures the ability to collect energy over a wide range of wavelengths. Spatial arrangement and functional tuning of the different phycobiliproteins, which are mediated primarily by linker proteins, yield PBS that is efficient and versatile light-harvesting systems. In this review, we discuss the functional and spatial tuning of phycobiliproteins with a focus on linker proteins.

Over recent decades, bispecific antibodies (bsAbs) have garnered significant attention for their superior therapeutic efficacy compared to progenitor monoclonal antibodies, enabling innovative treatment strategies. Despite their potential, the development of bsAbs presents significant challenges, with structural stability playing a pivotal role in manufacturability, therapeutic performance, and safety. Among the factors influencing stability, the design and incorporation of molecular linkers are particularly critical. In this study, we investigated the structural stability and fragmentation profiles of a symmetric bispecific antibody (Sym-bsAb), targeting HER2 and CD3, under forced degradation conditions. The Sym-bsAb exhibited pronounced fragmentation under prolonged thermal stress, particularly when combined with high pH and salt conditions. Intact mass analysis identified key degradation events, including sequential clipping along G4S and G4 linkers, fragmentations at interchain cystinyl residues and cleavage at the C-terminal of asparagine residues. The identification of G4S and G4 linkers as vulnerable regions prone to clipping in Sym-bsAb provided valuable insights into the stability and manufacturability of bsAbs incorporating linker sequences, underscoring critical considerations for their development.

Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.

CRISPR diagnostics based on nucleic acid amplification faces barriers to its commercial use, such as contamination risks and insufficient sensitivity. Here, we propose a robust solution involving optochemical control of CRISPR RNA (crRNA) activation in CRISPR detection. Based on this strategy, recombinase polymerase amplification (RPA) and CRISPR-Cas12a detection systems can be integrated into a completely closed test tube. crRNA can be designed to be temporarily inactivated so that RPA is not affected by Cas12a cleavage. After the RPA reaction is completed, the CRISPR-Cas12a detection system is activated under rapid light irradiation. This photocontrolled, fully closed CRISPR diagnostic system avoids contamination risks and exhibits a more than two orders of magnitude improvement in sensitivity compared with the conventional one-pot assay. This photocontrolled CRISPR method was applied to the clinical detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, achieving detection sensitivity and specificity comparable to those of PCR. Furthermore, a compact and automatic photocontrolled CRISPR detection device was constructed.

Reversible cross‐linking of thermoplastic materials allows thermoplastic processing before and after cross‐linking, while improving the mechanical and thermal properties after cross‐linking during the use phase. Hence, reversible cross‐linking can play an important role in establishing circularity by enabling mechanical recycling of a cross‐linked material after de‐linking. This exploratory study investigates 1‐(5‐(Aminoethyl)‐2‐nitrophenyl)ethanol as a photolabile cross‐linker (PXL) for polyamide 6 (PA6). The PXL is melt‐mixed with PA6 in two concentrations and processed into samples, which are investigated by Dynamic Mechanical Analysis (DMA) and Differential Scanning Calorimetry (DSC) before and after UV‐exposure. The addition of the PXL increases the storage modulus from 1.585 MPa for neat PA6 to 2.550 MPa for PA6 with 3 wt.% PXL and 3.470 MPa for PA6 with 6 wt.% PXL, respectively. Exposure to UV radiation decreases the storage modulus with increasing exposure time. The crystallinity decreases from 33,32% for neat PA6 to 30,71% for PA6 with 3 wt.% PXL and to 29,71% for PA6 with 6 wt.% PXL When the samples with PXL are exposed to UV‐radiation, an increase in the crystallinity is observed. The results of this exploratory study indicate that PA6 can be cross‐linked with 1‐(5‐(Aminoethyl)‐2‐nitrophenyl)ethanol and that de‐linking through UV‐exposure is possible. This exploratory study investigates the reversible cross‐linking of polyamide 6 by the photolabile cross‐linker 1‐(5‐(Aminoethyl)‐2‐nitrophenyl)ethanol (PXL). The storage modulus of the material increases with increasing PXL content and decreases when the exposure time of the samples is increased. The crystallinity of the samples decreases with increasing PXL content and increases after exposing the samples to UV radiation.

Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours.