Israel Journal of Chemistry最新文献

Cytokines play a central role in regulating cell communication and signal transduction, since they influence processes such as immunity, hematopoiesis, inflammatory disease, cancer, neurological disorders, and tissue healing. Notably, certain cytokines have been used clinically as protein therapeutics for conditions such as cancer, autoimmune diseases, and viral infections. Despite their therapeutic potential, cytokines often pose challenges, including side effects, stability constraints, and suboptimal pharmacokinetics. To address these limitations, there is growing interest in using diverse modalities to develop alternative cytokines with enhanced properties and therapeutic benefits. Of these modalities, effective high-throughput screening of macrocyclic peptides enabled by RNA-based catalysis has emerged as a promising candidate method for the development of alternative cytokines. Here, we focus on the development of cytokine alternatives using various approaches and explore prospects for their future use as therapeutic agents.

Cyclotides are ultra-stable peptides originally discovered in plants based on their medicinal applications. Their natural function is as host defence agents. They are amenable to chemical synthesis for use as scaffolds for drug design applications. Cyclotides comprise ~30 amino acids and in addition to having a head-to-tail cyclic backbone, incorporate six conserved cystine residues connected in a cystine knot motif. The cyclic backbone and cystine knot contribute to their exceptional resistance to proteases or thermal denaturation, making them useful scaffolds for drug design applications. The backbone segments, or loops, between the conserved cysteine residues are amenable to combinatorial variation in native cyclotides and have also been used to incorporate selected bioactive peptide epitopes into a range of synthetic cyclotides and cyclotide-like scaffolds. In the past this was largely done via low throughput structure-based design approaches, but the discovery of novel cyclotide binders has been greatly enhanced by the use of combinatorial display approaches on cyclotide scaffolds using phage, bacterial, yeast and mRNA technologies, as reviewed herein.

Aminoacyl-tRNA synthetases (aaRSs) maintain translational fidelity by ensuring the formation of correct aminoacyl-tRNA pairs. Numerous point mutations in human aaRSs have been linked to disease phenotypes. Structural studies of aaRSs from human pathogens encoding unique domains support these enzymes as potential candidates for therapeutics. Studies have shown that the identity of tRNA pools in cells changes between different cell types and under stress conditions. While traditional radioactive aminoacylation analyses can determine the effect of disease-causing mutations on aaRS function, these assays are not amenable to drug discovery campaigns and do not take into account the variability of the intracellular tRNA pools. Here, we review modern techniques to characterize aaRS activity in vitro and in cells. The cell-based approaches analyse the aminoacyl-tRNA pool to observe trends in aaRS activity and fidelity. Taken together, these approaches allow high-throughput drug screening of aaRS inhibitors and systems-level analyses of the dynamic tRNA population under a variety of conditions and disease states.

In this study, the occurrence of Diels–Alder reaction of cyclopentadiene yielding dicyclopentadiene within a confined closed space provided by octa acid (OA) in water at room temperature is established. The Diels–Alder reaction within the OA capsule occurs at least 2000 times faster than in water. Catalysis of Diels–Alder reaction by hosts such as cyclodextrin, cucurbituril, and Fujita's Pd nano–host occurs in water. Despite their similarity, these three hosts provide an open environment where the reactant molecules are exposed to aqueous environment. The only fully closed host known to catalyze the Diels–Alder reaction in water is OA. Although Rebek's host is established to catalyze Diels–Alder reaction it occurs in an organic solvent. The closed environment explored in this presentation provides an opportunity to better understand the origin of non–covalent catalysis in a restricted space and in water. Because the product binds stronger than the reactant, disappointingly, the capsule can't be recycled. We recognize that this aspect needs to be addressed for the OA capsule to become synthetically useful. We are in the process of understanding the origin of catalysis and finding ways to make reaction recyclable.

This review navigates the evolving landscape of N6-methyladenosine (m6A) research approaches, emphasizing the importance of advanced technology in understanding RNA epigenetics. Beginning with the fundamentals of m6A and the need for high- throughput methods, the investigation progresses from low-throughput approaches to high-throughput technologies, encompassing antibody-dependent and antibody-free sequencing methods, as well as nanopore-based direct mRNA sequencing and computation methods for m6A detection. Spatial techniques and imaging tools for m6A are also introduced in addition. The discussion of their special applications emphasizes the biological significance of absolute quantification, single-nucleotide resolution, single-molecule detection, and single-cell profiling. The review concludes with a vision of ideal approaches that combine current technologies for comprehensive m6A sequencing, with the potential to further our understanding of gene regulation, cellular diversity, and their roles in health and disease.

Chemical Biology of Nucleic Acid Modifications Issue editor: Chun-Xiao Song, Guifang Jia, Seraphine Wegner, and Chengqi Yi. The cover picture highlights Chuan He's wide-ranging research contributions across chemical biology, nucleic acid chemistry, biology, and epigenetics. His work focused on understanding DNA and RNA modifications in gene regulation. His groundbreaking discovery of reversible RNA modification revealed a new mode of gene regulation by RNA alongside DNA — and protein-based epigenetic mechanisms, leading to the emergence of the epitranscriptomics field.

We are excited to present this special issue of the Israel Journal of Chemistry, which is dedicated to the prestigious Wolf Prize in Chemistry 2023 awarded to Chuan He for his “pioneering work elucidating the chemistry and functional consequences of RNA modification”. In honor of Chuan's remarkable achievements, this special issue features contributions from a number of his past trainees, collaborators, and colleagues. Focusing on “Chemical Biology of nucleic acid modifications,” this collection underscores Chuan's pioneering work in epigenetics and epitranscriptomics, which has transformed our understanding of DNA and RNA modifications, unlocking new paths for diagnostics and treatments.^{1, 2} We present a collection of 15 Research and Review Articles that demonstrate the wide-ranging impact of Chuan's work across chemical biology, nucleic acid chemistry, biology, epigenetics, biochemistry, and genomics.

The diverse chemical modifications in cellular DNA and RNA, as Chuan has shown, add new dimensions to gene regulation that are crucial throughout development and disease progression. Chuan has been a trailblazer in applying chemical biology tools to mapping and understanding these modifications. This special issue opens with a research article from Chuan's lab, which presents a quantitative sequencing method for 5-formylcytosine (f⁵C) in RNA (R. Lyu et al. https://doi.org/10.1002/ijch.202300111). f⁵C is found in human tRNA and yeast mRNA, however, its transcriptome-wide distribution in mammals remained unexplored. Chuan's lab developed f⁵C-seq based on pic-borane reduction to map f⁵C transcriptome-wide and advanced our understanding of f⁵C in human and mouse cells. The research paper on f⁵C sequencing is complemented by a review from Cheng and coworkers, summarizing recent advances in f⁵C detection methods through selective chemical labeling, enrichment, and sequencing (X. Wang et al. https://doi.org/10.1002/ijch.202300178).

N⁶-methyladenosine (m⁶A) is the most common mRNA modification in eukaryotes. Chuan's lab made a landmark discovery in 2011 by identifying the first RNA demethylase, FTO, which removes the methyl group from m⁶A.³ This discovery unveiled the concept of reversible RNA methylation and led to the birth of the epitranscriptomics field. Today, m⁶A has become the most extensively studied RNA modification. Reflecting its prevalence, five articles in this issue are dedicated to m⁶A, including two complementary review papers offer a comprehensive look at m⁶A research. The review by Tang and coworkers is centered on m⁶A detection methods (R. Ge et al. ijch.202300181R1, accepted), while the review by Zhao and coworkers focuses on the biological functions of m⁶A in gene regulation a

RNA methylation is a crucial epigenetic modification widely present in RNA molecules, and has been demonstrated to play significant roles in diverse biological processes. Advances in detection and sequencing technologies have facilitated the identification of RNA modification-related regulatory proteins and their corresponding biological functions. In this paper, we provide a brief overview of several RNA methylation, including N⁶-methyladenosine(m⁶A), 5-methylcytidine(m⁵C), N¹-methyladenosine(m¹A), N⁷-methylguanosine(m⁷G) and N⁶, 2’-O-dimethyladenosine(m⁶Am), about their regulatory proteins, distribution patterns and biological functions, and mainly outline the advantages and limitations of the representative sequencing techniques. Finally, we discuss the technological challenges and future perspectives in RNA transcriptomic field.

N⁶-methyladenosine (m⁶A) is the most abundant internal modification in mammalian messenger RNA (mRNA), constituting 0.1 %–0.4 % of total adenosine residues in the transcriptome. m⁶A regulates mRNA stability and translation, pre-mRNA splicing, miRNA biogenesis, lncRNA binding, and many other physiological and pathological processes. While the majority of m⁶As occur in a consensus motif of DRm⁶ACH (D=A/G/U, R=A/G, H=U/A/C), the presence of such a motif does not guarantee methylation. Different RNA copies transcribed from the same gene may be methylated to varying levels. Within a single transcript, m⁶As are not evenly distributed, showing an enrichment in long internal and terminal exons. These characteristics of m⁶A deposition call for sequencing methods that not only pinpoint m⁶A sites at base resolution, but also quantitate the abundance of methylation across different RNA copies. In this review, we summarize existing m⁶A profiling methods, with an emphasis on next generation sequencing-(NGS−)based, site-specific, and quantitative methods, as well as several emerging single-cell methods.