Antibacterial resistance is a severe threat to modern medicine and human health. To stay ahead of constantly-evolving bacteria we need to expand our arsenal of effective antibiotics. As such, antisense therapy is an attractive approach. The programmability allows to in principle target any RNA sequence within bacteria, enabling tremendous selectivity. In this Tutorial Review we provide guidelines for devising effective antibacterial antisense agents and offer a concise perspective for future research. We will review the chemical architectures of antibacterial antisense agents with a special focus on the delivery and target selection for successful antisense design. This Tutorial Review will strive to serve as an essential guide for antibacterial antisense technology development.
Altered redox metabolism is one of the hallmarks of tumor cells, which not only contributes to tumor proliferation, metastasis, and immune evasion, but also has great relevance to therapeutic resistance. Therefore, regulation of redox metabolism of tumor cells has been proposed as an attractive therapeutic strategy to inhibit tumor growth and reverse therapeutic resistance. In this respect, nanomedicines have exhibited significant therapeutic advantages as intensively reported in recent studies. In this review, we would like to summarize the latest advances in nanomaterial-assisted strategies for redox metabolic regulation therapy, with a focus on the regulation of redox metabolism-related metabolite levels, enzyme activity, and signaling pathways. In the end, future expectations and challenges of such emerging strategies have been discussed, hoping to enlighten and promote their further development for meeting the various demands of advanced cancer therapies. It is highly expected that these therapeutic strategies based on redox metabolism regulation will play a more important role in the field of nanomedicine.
Regulated cell death is a fate of cells in (patho)physiological conditions during which extrinsic or intrinsic signals or redox equilibrium pathways following infection, cellular stress or injury are coupled to cell death modalities like apoptosis, necroptosis, pyroptosis or ferroptosis. An immediate survival response to cellular stress is often induction of autophagy, a process that deals with removal of aggregated proteins and damaged organelles by a lysosomal recycling process. These cellular processes and their regulation are crucial in several human diseases. Exploiting high-throughput assays which discriminate distinct cell death modalities and autophagy are critical to identify potential therapeutic agents that modulate these cellular responses. In the past few years, luciferase-based assays have been widely developed for assessing regulated cell death and autophagy pathways due to their simplicity, sensitivity, known chemistry, different spectral properties and high-throughput potential. Here, we review basic principles of bioluminescent reactions from a mechanistic perspective, along with their implication in vitro and in vivo for probing cell death and autophagy pathways. These include applying luciferase-, luciferin-, and ATP-based biosensors for investigating regulated cell death modalities. We discuss multiplex bioluminescence platforms which simultaneously distinguish between the various cell death phenomena and cellular stress recovery processes such as autophagy. We also highlight the recent technological achievements of bioluminescent tools for the prediction of drug effectiveness in pathways associated with regulated cell death.
The development of methodology for attaching ligand binding sites to proteins of interest has accelerated biomedical science. Such protein tags have widespread applications as well as properties that significantly limit their utility. This review describes the mechanisms and applications of supramolecular systems comprising the synthetic receptors cucurbit[7]uril (Q7) or cucurbit[8]uril (Q8) and their polypeptide ligands. Molecular recognition of peptides and proteins occurs at sites of 1-3 amino acids with high selectivity and affinity via several distinct mechanisms, which are supported by extensive thermodynamic and structural studies in aqueous media. The commercial availability, low cost, high stability, and biocompatibility of these synthetic receptors has led to the development of myriad applications. This comprehensive review compiles the molecular recognition studies and the resulting applications with the goals of providing a valuable resource to the community and inspiring the next generation of innovation.
Constructing highly proficient C-X (X = O, N, S, etc.) and C-C bonds by leveraging TMs (transition metals) (Fe, Cu, Pd, Rh, Au, etc.) and enzymes to catalyze carbene insertion into X-H/C(sp2)-H is a highly versatile strategy. This is primarily achieved through the in situ generation of metal carbenes from the interaction of TMs with diazo compounds. Over the last few decades, significant advancements have been made, encompassing a wide array of X-H bond insertions using various TMs. These reactions typically favor a stepwise ionic pathway where the nucleophilic attack on the metal carbene leads to the generation of a metal ylide species. This intermediate marks a critical juncture in the reaction cascade, presenting multiple avenues for proton transfer to yield the X-H inserted product. The mechanism of C(sp2)-H insertion reactions closely resembles those of X-H insertion reactions and thus have been included here. A major development in carbene insertion reactions has been the use of engineered enzymes as catalysts. Since the seminal report of a non-natural "carbene transferase" by Arnold in 2013, "P411", several heme-based enzymes have been reported in the literature to catalyze various abiological carbene insertion reactions into C(sp2)-H, N-H and S-H bonds. These enzymes possess an extraordinary ability to regulate the orientation and conformations of reactive intermediates, facilitating stereoselective carbene transfers. However, the absence of a suitable stereochemical model has impeded the development of asymmetric reactions employing a lone chiral catalyst, including enzymes. There is a pressing need to investigate alternative mechanisms and models to enhance our comprehension of stereoselectivity in these processes, which will be crucial for advancing the fields of asymmetric synthesis and biocatalysis. The current review aims to provide details on the mechanistic aspects of the asymmetric X-H and C(sp2)-H insertion reactions catalyzed by Fe, Cu, Pd, Rh, Au, and enzymes, focusing on the detailed mechanism and stereochemical model. The review is divided into sections focusing on a specific X-H/C(sp2)-H bond type catalyzed by different TMs and enzymes.