Front Cover: Chemoselective Labeling and Immobilization of Phosphopeptides with Phosphorimidazolide Reagents (ChemBioChem 4/2023)

Protein phosphorylation is one of the most ubiquitous post-translational modifications, regulating numerous essential processes in cells. Accordingly, the large-scale annotation of phosphorylation sites continues to provide central insight into the regulation of signaling networks. The global analysis of the phosphoproteome typically relies on mass spectrometry analysis of phosphopeptides, with an enrichment step necessary due to the sub-stoichiometric nature of phosphorylation. Several affinity-based methods and chemical modification strategies have been developed to date, but the choice of enrichment method can have a considerable impact on the results. Here, we show that a biotinylated, photo-cleavable phosphorimidazolide reagent permits the immobilization and subsequent cleavage of phosphopeptides. The method is capable of the capture and release of phosphopeptides of varying characteristics, and this mild and selective strategy expands the current repertoire for phosphopeptide chemical modification with the potential to enrich and identify new phosphorylation sites in the future.     

Perfluorocarbons in Chemical Biology

Perfluorocarbons, saturated carbon chains in which all the hydrogen atoms are replaced with fluorine, form a separate phase from both organic and aqueous solutions. Though perfluorinated compounds are not found in living systems, they can be used to modify biomolecules to confer orthogonal behavior within natural systems, such as improved stability, engineered assembly, and cell-permeability. Perfluorinated groups also provide handles for purification, mass spectrometry, and ¹⁹F NMR studies in complex environments. Herein, we describe how the unique properties of perfluorocarbons have been employed to understand and manipulate biological systems.     

Chemical Biology Towards Precision Medicine

Organic chemistry is primed to fill a much-needed gap in our understanding of human biology and disease on the one hand and our ability to treat disease effectively on the other. The key challenge is to discover compounds having the novel mechanisms of action demanded by these new patient-derived insights.     

几种化学药剂对水绵的生物活性测定

简要介绍了水绵的生物学特性及发生情况。室内初步研究了硫酸铜、三苯基醋酸锡及两者薯瘟锡混剂对水绵的生物活性。结果表明,三苯基醋酸锡对水绵的防除效果最好,在70ga．i．／hm^2剂量下对水绵的防效可达90％,其次是三苯基醋酸锡与硫酸铜混剂,再次是硫酸铜。     

浅谈化学生物学课程教学的探索与实践

化学生物学课程作为一门重要的专业课,在教学过程中面临着教材难选、不易讲授、教学效果难衡量等困难。结合自身的教学实践,文章从教学内容,教学方式及成绩考核三方面总结了一些经验,探索了一些行之有效的具体教学措施,以期更好地激发学生的学习兴趣、培养专业思维模式、提高学习效率,从而获得更好的教学效果。     

Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis

In the last few years, more and more scientists have suggested and confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. This is particularly interesting for a better understanding of processes that occur in the development and progression of various diseases. Appearing on the preclinical stages of diseases, epigenetic aberrations may be prominent biomarkers. Being dynamic and reversible, epigenetic modifications could become targets for a novel option for therapy. Therefore, in this review, we are focusing on histone modifications and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.     

EFMC,Medicinal Chemistry and Chemical Biology in Europe

This article is a reflection on the development of medicinal chemistry and chemical biology in Europe, and how the European Federation for Medicinal Chemistry (EFMC) helps the scientific community address its changing scope in a proactive manner. Networking, knowledge exchange and representation, as well as the acceptance and integration of novel scientific developments, are keys to a healthy and dynamic scientific community. This article also reviews some of the forces that shape the medicinal chemistry and chemical biology continuum, including cross-fertilization, digitalization, and the outsourcing of synthetic and characterization work to focus on productivity and scientific excellence.     

Epigenetic Deregulation of MicroRNAs in Rhabdomyosarcoma and Neuroblastoma and Translational Perspectives

Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed.     

Substrate Scope for Human Histone Lysine Acetyltransferase KAT8

Biomedically important histone lysine acetyltransferase KAT8 catalyses the acetyl coenzyme A-dependent acetylation of lysine on histone and other proteins. Here, we explore the ability of human KAT8 to catalyse the acetylation of histone H4 peptides possessing lysine and its analogues at position 16 (H4K16). Our synthetic and enzymatic studies on chemically and structurally diverse lysine mimics demonstrate that KAT8 also has a capacity to acetylate selected lysine analogues that possess subtle changes on the side chain and main chain. Overall, this work highlights that KAT8 has a broader substrate scope beyond natural lysine, and contributes to the design of new chemical probes targeting KAT8 and other members of the histone lysine acetyltransferase (KAT) family.     

Chemical Translational Biology: Redefining Druggability of Protein-Protein Interactions

Chemical biologists use chemical tools to answer biological questions. The translational application of these principles has led to an explosion in the discovery and druggability of new protein targets, including protein-protein interactions (PPIs). Proteins tend to interact with other macromolecules using relatively large and featureless binding surfaces, which has hampered traditional drug discovery efforts, particularly for interactions with weaker affinity. In this article, I discuss several emerging strategies for targeting PPIs, including computational and structural methods and novel screening approaches. In particular, I focus on hijacking intrinsic protein allosteric pathways for the discovery and design of small-molecule and peptide ligands.     

A Personal Perspective on Chemical Biology: Before the Beginning

This perspective represents a brief personal account of early days before “chemical biology” emerged as a field of inquiry. Imagine a time when oligomers of DNA could not be synthesized and the order of the TACG letters in DNA could not be sequenced. Even the high resolution structure of the DNA double helix was not yet determined. 1975 was a time when there was a deep chasm between chemistry and biology. Chemists with precise knowledge of all the atoms in natural product architectures looked with dismay at the imprecise messy world of biology. Water was to be avoided! My view was that the power of synthetic organic chemistry should be used to create function, synthesis with a purpose. Our organic group at Caltech would embrace molecular recognition of biologics in water as a frontier for chemistry. We dreamed of inventing small molecules that would control the activity of macromolecules such as DNA, proteins and carbohydrates in living cells. We chemists would sky dive into the messy world of biology.     

Identifying Small‐Molecule Binding Sites for Epigenetic Proteins at Domain–Domain Interfaces

Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.     

Chemical Biology Tools To Investigate Malaria Parasites

Parasitic diseases like malaria tropica have been shaping human evolution and history since the beginning of mankind. After infection, the response of the human host ranges from asymptomatic to severe and may culminate in death. Therefore, proper examination of the parasite's biology is pivotal to deciphering unique molecular, biochemical and cell biological processes, which in turn ensure the identification of treatment strategies, such as potent drug targets and vaccine candidates. However, implementing molecular biology methods for genetic manipulation proves to be difficult for many parasite model organisms. The development of fast and straightforward applicable alternatives, for instance small-molecule probes from the field of chemical biology, is essential. In this review, we will recapitulate the highlights of previous molecular and chemical biology approaches that have already created insight and understanding of the malaria parasite Plasmodium falciparum. We discuss current developments from the field of chemical biology and explore how their application could advance research into this parasite in the future. We anticipate that the described approaches will help to close knowledge gaps in the biology of P. falciparum and we hope that researchers will be inspired to use these methods to gain knowledge – with the aim of ending this devastating disease.     

Multiplexed Delivery of Synthetic (Un)Conjugatable Ubiquitin and SUMO2 Enables Simultaneous Monitoring of Their Localization and Function in Live Cells

Ubiquitin (Ub) and its related small Ub like modifier (SUMO) are among the most influential protein post-translational modifications in eukaryotes. Unfortunately, visualizing these modifications in live cells is a challenging task. Chemical protein synthesis offers great opportunities in studying and further understanding Ub and SUMO biology. Nevertheless, the low cell permeability of proteins limits these studies mainly for in vitro applications. Here, we introduce a multiplexed protein cell delivery approach, termed MBL (multiplexed bead loading), for simultaneous loading of up to four differentially labeled proteins with organic fluorophores. We applied MBL to visualize ubiquitination and SUMOylation events in live and untransfected cells without fluorescent protein tags or perturbation to their endogenous levels. Our study reveals unprecedented involvements of Ub and SUMO2 in lysosomes depending on conjugation states. We envision that this approach will improve our understanding of dynamic cellular processes such as formation and disassembly of membraneless organelles.