A divergent synthetic strategy for generating helical p53 peptides bearing functionalised staple linkages, allowing for efficient optimisation of cellular activity.

Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel 'pseudo-natural product' classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we have identified design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small molecule discovery. Main textThe search for small molecules with novel molecular scaffolds that display unprecedented or unexpected biological activity greatly benefits from insights gained from compound classes that are biologically relevant by definition, such as natural products (NPs). NPs have served as an inspiration and resource in drug discovery and chemical biology 1 and constitute chemical matter pre-validated by evolution. 2 Libraries based on natural product structure or more relaxed chemical and structural considerations have been developed through different approaches. At one end of the spectrum NP-derived compound collections may be synthesised directly from readily available NPs, e.g. by derivatisations at pre-existing reactive sites, and by ringdistortion and/or -modification approaches ("complexity to diversity"; CtD) as first demonstrated by Hergenrother. 3,4 For instance, abietic acid was converted into a chemically diverse collection of complex compounds by means of 3-6 transformations, including ring opening-, expansion-and contraction sequences 4 (Figure 1a), whilst ring-distortion of the alkaloid quinidine yielded novel inhibitors of autophagy. 5 In an alternative approach complex polycyclic scaffolds that exhibit NP characteristics and properties are directly synthesised and distorted. For instance, tropane-containing compounds delivered multiple new scaffolds not found within NPs, several of which were found to be novel bromodomain binders. 6

Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.

Chemical genetics can be defined as the study of biological systems using small molecule tools. Cell permeable and selective small molecules modulate gene product function rapidly, reversibly and can be administered conditionally in either a cellular or organismal context. The small molecule approach provides exacting temporal and quantitative control and is therefore an extremely powerful tool for dissecting biological processes. This tutorial review has been written to introduce the subject to a broad audience and highlights recent developments within the field in four key areas of biology: modulating protein-protein interactions, malaria research, hepatitis C virus research, and disrupting RNA interference pathways.

The deeply red-colored natural compound prodigiosin is a representative of the prodiginine alkaloid family, which possesses bioactivities as antimicrobial, antitumor, and antimalarial agents. Various bacteria including the opportunistic human pathogen Serratia marcescens and different members of the Streptomycetaceae and Pseudoalteromonadaceae produce prodiginines. In addition, these microbes generally accumulate many structurally related alkaloids making efficient prodiginine synthesis and purification difficult and expensive. Furthermore, it is known that structurally different natural prodiginine variants display differential bioactivities. In the herein described mutasynthesis approach, 13 different derivatives of prodigiosin were obtained utilizing the GRAS (generally recognized as safe) classified strain Pseudomonas putida KT2440. Genetic engineering of the prodigiosin pathway together with incorporation of synthetic intermediates thus resulted in the formation of a so far unprecedented structural diversity of new prodiginine derivatives in P. putida. Furthermore, the formed products allow reliable conclusions regarding the substrate specificity of PigC, the final condensing enzyme in the prodigiosin biosynthesis pathway of S. marcescens. The biological activity of prodigiosin toward modulation of autophagy was preserved in prodiginine derivatives. One prodiginine derivative displayed more potent autophagy inhibitory activity than the parent compound or the synthetic clinical candidate obatoclax.

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Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis Nature Chemical Biology, 15 (7): 710-720 Editorial SummaryThe cholesterol transfer protein GRAMD1A was identified as the target of the autophagy inhibitors autogramin-1 and 2. GRAMD1A is required for autophagosome biogenesis, and autogramins represent tool compounds for studying this process. AbstractAutophagy mediates the degradation of damaged proteins, organelles and pathogens and plays a key role in health and disease. The identification of new mechanisms involved in autophagy regulation is of major interest. In particular little is known about the roles of lipids and lipid binding proteins in the early steps of autophagosome biogenesis. Through target agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a novel autophagy inhibitor class. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain containing protein 1A (GRAMD1A), which had not been implicated in autophagy before, and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a novel biological function of GRAMD1A and a new role for cholesterol in autophagy.