Covering: 2014 to 2023 for metabolomics, 2002 to 2023 for information visualizationLC-MS/MS-based untargeted metabolomics is a rapidly developing research field spawning increasing numbers of computational metabolomics tools assisting researchers with their complex data processing, analysis, and interpretation tasks. In this article, we review the entire untargeted metabolomics workflow from the perspective of information visualization, visual analytics and visual data integration. Data visualization is a crucial step at every stage of the metabolomics workflow, where it provides core components of data inspection, evaluation, and sharing capabilities. However, due to the large number of available data analysis tools and corresponding visualization components, it is hard for both users and developers to get an overview of what is already available and which tools are suitable for their analysis. In addition, there is little cross-pollination between the fields of data visualization and metabolomics, leaving visual tools to be designed in a secondary and mostly fashion. With this review, we aim to bridge the gap between the fields of untargeted metabolomics and data visualization. First, we introduce data visualization to the untargeted metabolomics field as a topic worthy of its own dedicated research, and provide a primer on cutting-edge visualization research into data visualization for both researchers as well as developers active in metabolomics. We extend this primer with a discussion of best practices for data visualization as they have emerged from data visualization studies. Second, we provide a practical roadmap to the visual tool landscape and its use within the untargeted metabolomics field. Here, for several computational analysis stages within the untargeted metabolomics workflow, we provide an overview of commonly used visual strategies with practical examples. In this context, we will also outline promising areas for further research and development. We end the review with a set of recommendations for developers and users on how to make the best use of visualizations for more effective and transparent communication of results.

Covering 2010-April 2024There have been tremendous new discoveries and developments since 2010 in anticancer research based on marine cyanobacteria. Marine cyanobacteria are prolific sources of anticancer natural products, including the tubulin agents dolastatins 10 and 15 which were originally isolated from a mollusk that feeds on cyanobacteria. Decades of research have culminated in the approval of six antibody-drug conjugates (ADCs) and many ongoing clinical trials. Antibody conjugation has been enabling for several natural products, particularly cyanobacterial cytotoxins. Targeting tubulin dynamics has been a major strategy, leading to the discovery of the gatorbulin scaffold, acting on a new pharmacological site. Cyanobacterial compounds with different mechanisms of action (MOA), targeting novel or validated targets in a range of organelles, also show promise as anticancer agents. Important advances include the development of compounds with novel MOA, including apratoxin and coibamide A analogues, modulating cotranslational translocation at the level of Sec61 in the endoplasmic reticulum, largazole and santacruzamate A targeting class I histone deacetylases, and proteasome inhibitors based on carmaphycins, resembling the approved drug carfilzomib. The pipeline extends with SERCA inhibitors, mitochondrial cytotoxins and membrane-targeting agents, which have not yet advanced clinically since the biology is less understood and selectivity concerns remain to be addressed. In addition, efforts have also focused on the identification of chemosensitizing and antimetastatic agents. The review covers the state of current knowledge of marine cyanobacteria as anticancer agents with a focus on the mechanism, target identification and potential for drug development. We highlight the importance of solving the supply problem through chemical synthesis as well as illuminating the biological activity and in-depth mechanistic studies to increase the value of cyanobacterial natural products to catalyze their development.

Covering: 1962 to 2023Drimane (hydro)quinones biosynthetically arise from the combination of drimane-type terpenoids with phenols or equivalents. Since the isolation of siccanin in 1962 (structure identified in 1967), over 200 natural drimane (hydro)quinones have been reported. They are widespread with remarkably diverse architectures and biological functions, which are achieved by varying either the drimane subunit, hydroquinone segment, or the fusion types of drimane and hydroquinone segment both of them. This type of natural products has drawn increasing attention in the discovery of novel pharmaceutical leads. Enormous efforts have been devoted to developing efficient and divergent synthesis approaches to facilitate the SAR study of drimane (hydro)quinones, aiming for more promising functional leads. This review is arranged mainly in terms of scaffold types of drimane (hydro)quinones and further categorized on the basis of biological functions. The mechanisms of action are also briefly discussed. Synthetic methods are categorized according to the strategies forging the Csp-Csp linker between drimane segments and (hydro)quinone subunits.

Covering up to September 2024Collembola, commonly known as springtails, are abundant and important members of soil ecosystems. Due to their small size and hidden life, not much is known about their secondary metabolites. This chemistry is remarkably different from that of insects, with which they share a common ancestor, although they diverged already around 450 mya. Here we describe what is known so far, mainly compounds for chemical defence and cuticular lipids, as well as chemical signals. The uniqueness of the structures found is striking, many of which are not known from other natural sources. These include polychlorinated benzopyranones, small alkaloids, hetero-substituted aromatic compounds, and a diverse terpene chemistry, including highly branched compounds.

Covering: 2010 to 2023Cyanobacterial natural products are a diverse group of molecules with promising biotechnological applications. This review examines the chemical diversity of 995 cyanobacterial metabolites reported from 2010 to 2023. A computational analysis using similarity networking was applied to visualize the chemical space and to compare the diversity of cyanobacterial metabolites among taxonomic orders and environmental sources. Key examples are highlighted, detailing their sources, biological activities, and discovery processes.

Covering: 1974 to 2024Human microbiota consist of a diverse array of microorganisms, such as bacteria, Eukarya, archaea, and viruses, which populate various parts of the human body and live in a cooperatively beneficial relationship with the host. They play a crucial role in supporting the functional balance of the microbiome. The coevolutionary progression has led to the development of specialized metabolites that have the potential to substitute traditional antibiotics in combating global health challenges. Although there has been a lot of research on the human microbiota, there is a considerable lack of understanding regarding the wide range of peptides that these microbial populations produce. Particularly noteworthy are the antibiotics that are uniquely produced by the human microbiome, especially by bacteria, to protect against invasive infections. This review seeks to fill this knowledge gap by providing a thorough understanding of various peptides, along with their in-depth biological importance in terms of human disorders. Advancements in genomics and the understanding of molecular mechanisms that control the interactions between microbiota and hosts have made it easier to find peptides that come from the human microbiome. We hope that this review will serve as a basis for developing new therapeutic approaches and personalized healthcare strategies. Additionally, it emphasizes the significance of these microbiota in the field of natural product discovery and development.

Covering: up to 2024Fungal pathogens are a major threat to public health, with emerging resistance to all three classes of antifungals that are currently available and increased incidence of invasive fungal infections among hospitalized patients. Ibrexafungerp is a semi-synthetic analog of enfumafungin and the first antifungal agent approved in more than 20 years since the launch of caspofungin, the first of echinocandins. This new drug approval was made possible after a long arduous journey lasting 25 years by dedicated and talented medicinal chemists from two companies that undertook tedious atom-by-atom chemical modification of the natural product enfumafungin, a glycosylated fernane-type triterpenoid isolated from the fungus . This highlight will cover the discovery of enfumafungin, its biosynthesis and the characterisation of its antifungal profile and mode of action that led to the development of ibrexafungerp. We will discuss the challenges encountered during this long preclinical program and the clinical trial validation of this first-in-class oral antifungal approved to treat vulvovaginal candidiasis with an enormous therapeutic potential to treat future major threatening drug-resistant fungal pathogens.

Covering: 2016 to the end of 2024This highlight article aims to provide a perspective on the challenges that novel biotechnological processes face in the biomanufacturing of natural products (NPs) whose biosynthesis pathways rely on cytochrome P450 monooxygenases. This enzyme superfamily is one of the most versatile in the biosynthesis of a plethora of NPs finding use across the food, nutrition, medicine, chemical and cosmetics industries. These enzymes often exhibit excellent regio- and stereoselectivity, but they can suffer from low activity and instability, which are serious issues impairing the development of high performing bioprocesses. We start with a brief introduction to industrial biotechnology and the importance of looking for alternative means for producing NPs independently from unsustainable fossil fuels or plant extractions. We then discuss the challenges and implemented solutions during the development of commercial NP processes focusing on the P450-dependent steps primarily in yeast cell factories. Our main focus is to highlight the challenges often encountered when utilizing P450-dependent NP pathways, and how protein engineering can be used for debottlenecking them. Finally, we briefly touch upon the importance of artificial intelligence and machine learning for guiding engineering efforts.

Covering: up to 2024.For many years, the value of complex polyketides lay in their medical properties, including their antibiotic and antifungal activities, with little consideration paid to their native functions. However, more recent evidence gathered from the study of inter-organismal interactions has revealed the influence of these metabolites upon the ecological adaptation and distribution of their hosts, as well as their modes of communication. The increasing number of sequenced genomes and associated transcriptomes has also unveiled the widespread occurrence of the underlying biosynthetic enzymes across all kingdoms of life, and the important contributions they make to physiological events specific to each organism. This review depicts the diversity of roles fulfilled by type I polyketides, particularly in light of studies carried out during the last decade, providing an initial overall picture of their diverse functions.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as dicitrinol A from .

Covering: up to 2024The prompt identification of (bio)active natural products (NPs) from complex mixtures poses a significant challenge due to the presence of numerous compounds with diverse structures and (bio)activities. Thus, this review provides an overview of current and emerging tools and strategies for the identification of (bio)active NPs in complex mixtures. Traditional approaches of bioassay-guided fractionation (BGF), followed by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis for compound structure elucidation, continue to play an important role in the identification of active NPs. However, recent advances (2018-2024) have led to the development of novel techniques such as (bio)chemometric analysis, dereplication and combined approaches, which allow efficient prioritization for the elucidation of (bio)active compounds. For researchers involved in the search for bioactive NPs and who want to speed up their discoveries while maintaining accurate identifications, this review highlights the strengths and limitations of each technique and provides up-to-date insights into their combined use to achieve the highest level of confidence in the identification of (bio)active natural products from complex matrices.

Covering: up to March 2024.Microbial natural products have historically been a cornerstone for the discovery of therapeutic agents. Advanced (meta)genome sequencing technologies have revealed that microbes harbor far greater biosynthetic capabilities than previously anticipated. However, despite the application of CRISPR/Cas-based gene editing and high-throughput technologies to activate silent biosynthetic gene clusters, the rapid identification of new natural products has not led to a proportional increase in the discovery rate of lead compounds or drugs. A crucial issue in this gap may be insufficient knowledge about the inherent biological and physiological functions of microbial natural products. Addressing this gap necessitates recognizing that the generation of functional natural products is deeply rooted in the interactions between the producing microbes and other (micro)organisms within their ecological contexts, an understanding that is essential for harnessing their potential therapeutic benefits. In this review, we highlight the discovery of functional microbial natural products from diverse niches, including those associated with humans, nematodes, insects, fungi, protozoa, plants, and marine animals. Many of these findings result from an organismic-interaction-guided strategy using multi-omic approaches. The current importance of this topic lies in its potential to advance drug discovery in an era marked by increasing antimicrobial resistance.

Covering: up to June 2024Benzylisoquinoline alkaloids (BIAs) represent a diverse class of plant specialized metabolites derived from L-tyrosine, exhibiting significant pharmacological properties such as anti-microbial, anti-spasmodic, anti-cancer, cardiovascular protection, and analgesic effects. The industrial production of valuable BIAs relies on extraction from plants; however, challenges concerning their low concentration and efficiency hinder drug development. Hence, alternative approaches, including biosynthesis and chemoenzymatic synthesis, have been explored. Model species like and have played a key role in unraveling the biosynthetic pathways of BIAs; however, many aspects, particularly modified steps like oxidation and methylation, remain unclear. Critical enzymes, , CYP450s and methyltransferases, play a substantial role in BIA backbone formation and modification, which is essential for understanding the origin and adaptive evolution of these plant specialized metabolites. This review comprehensively analyzes the structural diversity of reported BIAs and their distribution in plant lineages. In addition, the progress in understanding biosynthesis, evolution, and catalytic mechanisms underlying BIA biosynthesis is summarized. Finally, we discuss the progress and challenges in metabolic engineering, providing valuable insights into BIA drug development and the sustainable utilization of BIA-producing plants.

Covering: 2019 to 2023Isoquinoline alkaloids, an important class of -based heterocyclic compounds, have attracted considerable attention from researchers worldwide. To follow up on our prior review (covering 2014-2018) and present the progress of this class of compounds, this review summarizes and provides updated literature on novel isoquinoline alkaloids isolated during the period of 2019-2023, together with their biological activity and underlying mechanisms of action. Moreover, with the rapid development of synthetic modification strategies, the synthesis strategies of isoquinoline alkaloids have been continuously optimized, and the total synthesis of these classes of natural products is reviewed critically herein. Over 250 molecules with a broad range of bioactivities, including antitumor, antibacterial, cardioprotective, anti-inflammatory, neuroprotective and other activities, are isolated and discussed. The total synthesis of more than nine classes of isoquinoline alkaloids is presented, and thirteen compounds constitute the first total synthesis. This survey provides new indications or possibilities for the discovery of new drugs from the original naturally occurring isoquinoline alkaloids.

Covering: 2016 to 2024Natural products, particularly cyclic peptides, are a promising source of bioactive compounds. Nonribosomal peptide synthetases (NRPSs) play a key role in biosynthesizing these compounds, which include antibiotic and anticancer agents, immunosuppressants, and others. Traditional methods of discovering natural products have limitations including cryptic biosynthetic gene clusters (BGCs), low titers, and currently unculturable organisms. This has prompted the exploration of alternative approaches. Synthetic-bioinformatic natural products (-BNPs) are one such alternative that utilizes bioinformatics techniques to predict nonribosomal peptides (NRPs) followed by chemical synthesis of the predicted peptides. This approach has shown promise, resulting in the discovery of a variety of bioactive compounds including peptides with antibacterial, antifungal, anticancer, and proteasome-stimulating activities. Despite the success of this approach, challenges remain especially in the accurate prediction of fatty acid incorporation, tailoring enzyme modifications, and peptide release mechanisms. Further work in these areas will enable the discovery of many bioactive peptides that are currently inaccessible.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as asperochone A from sp. MMC-2.

Covering: 2013 to 2023In an era where antimicrobial resistance severely threatens our ability to treat infections, the discovery of new drugs that belong to different chemical classes and/or bear original modes of action is urgently needed. In this case, diterpenoids comprise a productive field with a proven track record in providing new anti-infectives to tackle bacterial infections and malaria. This review highlights the potential of both naturally occurring and semi-synthetic bi- and tricyclic diterpenoids to become leads in search of new drugs to treat infections caused by bacteria, fungi, viruses and protozoan parasites. The literature from the last decade (2013-2023) is covered, focusing on naturally occurring and semi-synthetic bicyclic (labdanes and labdane-type) and tricyclic (all classes) diterpenoids, detailing their relevant biological activities in the context of infection, which are explained through structure-activity relationships.

Covering: up to August 2024Enzymes play an essential role in synthesizing value-added chemicals with high specificity and selectivity. Since enzymes utilize substrates derived from renewable resources, biocatalysis offers a pathway to an efficient bioeconomy with reduced environmental footprint. However, enzymes have evolved over millions of years to meet the needs of their host organisms, which often do not align with industrial requirements. As a result, enzymes frequently need to be tailored for specific industrial applications. Combining enzyme engineering with high-throughput screening has emerged as a key approach for developing novel biocatalysts, but several challenges are yet to be addressed. In this review, we explore emergent strategies and methods for isolating, creating, and characterizing enzymes optimized for bioproduction. We discuss fundamental approaches to discovering and generating enzyme variants and identifying those best suited for specific applications. Additionally, we cover techniques for creating libraries using automated systems and highlight innovative high-throughput screening methods that have been successfully employed to develop novel biocatalysts for natural product synthesis.

Covering: up to 2024Fe(II) and 2-oxoglutarate-dependent dioxygenases (Fe/2OG DOs) are a superfamily of enzymes that play important roles in a variety of catalytic reactions, including hydroxylation, ring formation, ring reconstruction, desaturation, and demethylation. Each member of this family has similarities in their overall structure, but they have varying specific differences, making Fe/2OG DOs attractive for catalytic diversity. With the advancement of current research, more Fe/2OG DOs have been discovered, and their catalytic scope has been further broadened; however, apart from hydroxylation, many reaction mechanisms have not been accurately demonstrated, and there is a lack of a systematic understanding of their molecular basis. Recently, an increasing number of X-ray structures of Fe/2OG DOs have provided new insights into the structural basis of their function and substrate-binding properties. This structural information is essential for understanding catalytic mechanisms and mining potential catalytic reactions. In this review, we summarize most of the Fe/2OG DOs whose structures have been resolved in recent years, focus on their structural features, and explore the relationships between various structural elements and unique catalytic mechanisms and their associated reaction type classification.

Covering: 1961 to 2024Discovering and identifying unique natural products/biosignatures (signatures that can be used as evidence for past or present life) that are abundant, and complex enough that they indicate robust evidence of life is a multifaceted process. One distinct category of biosignatures being explored is organic compounds. A subdivision of these compounds not yet readily investigated are volatile organic compound (VOCs). When assessing these VOCs as a group (volatilome) a fingerprint of all VOCs within an environment allows the complex patterns in metabolic data to be unravelled. As a technique already successfully applied to many biological and ecological fields, this paper explores how analysis of volatilomes in terrestrial extreme environments could be used to enhance processes (such as metabolomics and metagenomics) already utilised in life detection beyond Earth. By overcoming some of the complexities of collecting VOCs in remote field sites, a variety of lab based analytical equipment and techniques can then be utilised. Researching volatilomics in astrobiology requires time to characterise the patterns of VOCs. They must then be differentiated from abiotic (non-living) signals within extreme environments similar to those found on other planetary bodies (analogue sites) or in lab-based simulated environments or microcosms. Such an effort is critical for understanding data returned from past or upcoming missions, but it requires a step change in approach which explores the volatilome as a vital additional tool to current 'Omics techniques.

Covering: up to 2024This review showcases selected natural products, which are of high relevance to the craft of crop protection, including in its most recent aspects such as their non-cidal use as biostimulants in plant health. Focussing on the chemistry and associated structure-activity relationships that were disclosed, the review presents case studies from the recent chemical development of important natural products and compounds inspired by them for their use in the crop protection industry.