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Naoki Shirata

Bio: Naoki Shirata is an academic researcher from Tohoku University. The author has contributed to research in topics: Gene & Epigenomics. The author has an hindex of 3, co-authored 3 publications receiving 123 citations. Previous affiliations of Naoki Shirata include Iwate Medical University & Tokyo Institute of Technology.

Papers
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Journal ArticleDOI
TL;DR: This work has developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification of fungal polyketide intermediates and demonstrated an advanced method of using biosynthetic intermediates.
Abstract: The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.

64 citations

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TL;DR: Epigenetic manipulation of gene expression in Chaetomium indicum using a HDAC inhibitor led to the isolation of structurally diverse chaetophenols, and 3, 4 and 5 bear unprecedented polycyclic skeletons.

48 citations

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TL;DR: Spectroscopic methods, X-ray single crystal diffraction analysis, and VCD elucidated the absolute configurations of structures 1-6, and plausible biosynthetic pathways for 1-7 were proposed based on structural relationships.

41 citations


Cited by
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Journal ArticleDOI
TL;DR: This Review discusses the strategies that have been developed in bacteria and fungi to identify and induce the expression of silent BGCs, and briefly summarize methods for the isolation and structural characterization of their metabolic products.
Abstract: Microorganisms produce a wealth of structurally diverse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens; however, realizing this potential has been hampered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products.

692 citations

Journal ArticleDOI
TL;DR: This review provides an overview of various approaches to exploit the diversity of compounds for natural product‐based drug development, drawing upon a series of examples to illustrate each strategy.
Abstract: Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

167 citations

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TL;DR: This review highlights important and successful examples using OSMAC approaches, which covers changing medium composition and cultivation status, co-cultivation with other strain(s), adding enzyme inhibitor(s) and MSM biosynthetic precursor(s).
Abstract: Microbial secondary metabolites (MSMs) have played and continue to play a highly significant role in the drug discovery and development process. Genetically, MSM chemical structures are biologically synthesized by microbial gene clusters. Recently, however, the speed of new bioactive MSM discovery has been slowing down due to consistent employment of conventional cultivation and isolation procedure. In order to alleviate this challenge, a number of new approaches have been developed. The strategy of one strain many compounds (OSMAC) has been shown as a simple and powerful tool that can activate many silent biogenetic gene clusters in microorganisms to make more natural products. This review highlights important and successful examples using OSMAC approaches, which covers changing medium composition and cultivation status, co-cultivation with other strain(s), adding enzyme inhibitor(s) and MSM biosynthetic precursor(s). Available evidences had shown that variation of cultivation condition is the most effective way to produce more MSMs and facilitate the discovery of new therapeutic agents.

137 citations

Journal ArticleDOI
TL;DR: A design approach for the preparation of biologically relevant small-molecule libraries is discussed, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds.
Abstract: 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 identify design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small-molecule discovery.

99 citations

Journal ArticleDOI
TL;DR: Polyketides 1-6 were produced by a one strain-many compounds (OSMAC) approach using the endophytic fungus Dothideomycete sp.

98 citations