The semi-synthetic derivatization and biosynthetic studies of lincosamide antibiotics have been reported due to their unique structures and remarkable biological activities. In this review, the structure and biological activity of lincosamides, and enzymatic study of lincosamides biosynthesis will be summarized.

Abstract

Lincosamides are naturally occurring antibiotics isolated from Streptomyces sp. Currently, lincomycin A and its semisynthetic analogue clindamycin are used as clinical drugs. Due to their unique structures and remarkable biological activities, derivatizations of lincosamides via semi-synthesis and biosynthetic studies have been reported. This review summarizes the structures and biological activities of lincosamides, and the recent studies of lincosamide biosynthetic enzymes.

Positively charged or basic amino acid-derived cationic amphiphiles exhibit promising outcomes in drug and nucleic acid delivery. Among these, histidine-containing amphiphiles demonstrate the highest potential in this regard. Notably, the drug and nucleic acid delivery efficiency of these amphiphiles is directly proportional to the number of histidine moieties incorporated. These findings underscore the significance of histidine-rich structures in optimizing and enhancing the efficacy of drug and nucleic acid delivery systems.

Abstract

Leveraging liposomes for drug and nucleic acid delivery, though promising due to reduced toxicity and ease of preparation, faces challenges in stability and efficiency. To address this, we synthesized cationic amphiphiles from amino acids (arginine, lysine, and histidine). Histidine emerged as the superior candidate, leading to the development of three histidine-rich cationic amphiphiles for liposomes. Using the hydration method, we have prepared the liposomes and determined the optimal N/P ratios for lipoplex formation via gel electrophoresis. In vitro transfection assays compared the efficacy of our lipids to Fugene, while MTT assays gauged biocompatibility across cancer cell lines (MDA-MB 231 and MCF-7). The histidine-based lipid demonstrated marked potential in enhancing drug and nucleic acid delivery. This improvement stemmed from increased zeta potential, enhancing electrostatic interactions with nucleic acids and cellular uptake. Our findings underscore histidine‘s crucial role over lysine and arginine for effective delivery, revealing a significant correlation between histidine abundance and optimal performance. This study paves the way for histidine-enriched lipids as promising candidates for efficient drug and nucleic acid delivery, addressing key challenges in the field.

Small molecules have been widely utilized within the synthetic biology community as trigger input for regulating implemented genetic circuit in engineered mammalian cells. Here, we described the most commonly used small molecules and their associated genetic switches, employed to program cell behaviors, particularly within a cell and gene therapy context.

Abstract

Synthetic or natural small molecules have been extensively employed as trigger signals or inducers to regulate engineered gene circuits introduced into living cells in order to obtain desired outputs in a controlled and predictable manner. Here, we provide an overview of small molecules used to drive synthetic-biology-based gene circuits in mammalian cells, together with examples of applications at different levels of control, including regulation of DNA manipulation, RNA synthesis and editing, and protein synthesis, maturation, and trafficking. We also discuss the therapeutic potential of these small-molecule-responsive gene circuits, focusing on the advantages and disadvantages of using small molecules as triggers, the mechanisms involved, and the requirements for selecting suitable molecules, including efficiency, specificity, orthogonality, and safety. Finally, we explore potential future directions for translation of these devices to clinical medicine.

A biocatalytic process for synthesizing clinically important indole-based imidazo[1,2-a]pyridine derivatives using the α-amylase catalyzed Groebke-Blackburn-Bienayme (GBB) multicomponent reaction of 2-aminopyridine, indole-3-carboxaldehyde, and isocyanide has been developed. Further, α-amylase from Aspergillus oryzae was immobilized onto magnetic metal-organic framework (MOF) materials [Fe₃O₄@MIL-100(Fe)] to make it a robust and reusable catalyst for this transformation.

Abstract

The imidazo[1,2-a]pyridine scaffold has gained significant attention due to its presence as a lead structure in several commercially available pharmaceuticals like zolimidine, zolpidem, olprinone, soraprazan, etc. Further, indole-based imidazo[1,2-a]pyridine derivatives have been found interesting due to their anticancer and antibacterial activities. However, limited methods have been reported for the synthesis of indole-based imidazo[1,2-a]pyridines. In this study, we have successfully developed a biocatalytic process for synthesizing indole-based imidazo[1,2-a]pyridine derivatives using the α-amylase enzyme catalyzed Groebke-Blackburn-Bienayme (GBB) multicomponent reaction of 2-aminopyridine, indole-3-carboxaldehyde, and isocyanide. The generality and robustness of this protocol were shown by synthesizing differently substituted indole-based imidazo[1,2-a]pyridines in good isolated yields. Furthermore, to make α-amylase a reusable catalyst for GBB multicomponent reaction, it was immobilized onto magnetic metal-organic framework (MOF) materials [Fe₃O₄@MIL-100(Fe)] and found reusable up to four consecutive catalytic cycles without the significant loss in catalytic activity.

Creating new biochemistries in living organisms requires adaptation for learning how to use new resources, a process governed by genetic mutations. When fed with tryptophan analogs, Escherichia coli cells learned to repress their general stress response and other molecular bioprocesses. This discovery creates more opportunities for the incorporation of non-canonical amino acids with benefits in Xenobiology, Metabolic Engineering and Biocatalysis.

Abstract

The chemical evolution of a synthetic cell endowed with a synthetic amino acid as building block, analog to tryptophan, required the emergence of key mutations in genes involved in, inter alia, the general stress response, amino acid metabolism, stringent response, and chemotaxis. Understanding adaptation mechanisms to non-canonical biomass components will inform strategies for engineering synthetic metabolic pathways and cells.

Saraya and O'Flaherty report the use of a commercially available building block, typically used for chemical phosphorylation, to perform Tandem Oligonucleotide Synthesis (TOS). The TOS strategy allows the facile preparation of multiple DNA/RNA oligomers separated by a cleavable linker. The immolation of these linkers occurs during the standard ammonium hydroxide deprotection. (designed by Tiffany A. Mills). More information can be found in the Research Article by J. S. Saraya, D. K. O'Flaherty.

Versatile biotin-based tools are highlighted here for studying ubiquitin- and ubiquitin-like modifications in cells and organisms. These powerful proteomic methods can eventually be coupled with other chemical biology concepts (e. g. induced proximity pharmacology, targeted protein degradation, PROTACs, molecular glues, etc.) for addressing specificity and unraveling mechanisms in the complex ubiquitin signaling system. Created with BioRender.com.

Abstract

A complex code of cellular signals is mediated by ubiquitin and ubiquitin-like (Ub/UbL) modifications on substrate proteins. The so-called Ubiquitin Code specifies protein fates, such as stability, subcellular localization, functional activation or suppression, and interactions. Hundreds of enzymes are involved in placing and removing Ub/UbL on thousands of substrates, while the consequences of modifications and the mechanisms of specificity are still poorly defined. Challenges include rapid and transient engagement of enzymes and Ub/UbL interactors, low stoichiometry of modified versus non-modified cellular substrates, and protease-mediated loss of Ub/UbL in lysates. To decipher this complexity and confront the challenges, many tools have been created to trap and identify substrates and interactors linked to Ub/UbL modification. This review focuses on an assortment of biotin-based tools developed for this purpose (for example BioUbLs, UbL-ID, BioE3, BioID), taking advantage of the strong affinity of biotin-streptavidin and the stringent lysis/washing approach allowed by it, paired with sensitive mass-spectrometry-based proteomic methods. Knowing how substrates change during development and disease, the consequences of substrate modification, and matching substrates to particular UbL-ligating enzymes will contribute new insights into how Ub/UbL signaling works and how it can be exploited for therapies.

Epidithiodioxopiperazines (ETPs) alkaloids possess complex structures and exhibit a broad spectrum of biological activities. In this concept, we summarize the biosynthesis of α, α′- and α, β′-disulfide bridged ETPs and outline the catalytic machineries for the transannular disulfide construction. This will facilitate the medical and industrial applications of ETPs.

Abstract

Epidithiodioxopiperazine (ETP) alkaloids, featuring a 2,5-diketopiperazine core and transannular disulfide bridge, exhibit a broad spectrum of biological activities. However, the structural complexity has prevented efficient chemical synthesis and further clinical research. In the past few decades, many achievements have been made in the biosynthesis of ETPs. Here, we discuss the biosynthetic progress and summarize them as two comprehensible metabolic principles for better understanding the complex pathways of α, α′- and α, β′-disulfide bridged ETPs. Specifically, we systematically outline the catalytic machineries to install α, α′- and α, β′-disulfide by flavin-containing oxygenases. This concept would contribute to the medical and industrial applications of ETPs.