Design and Biosynthesis of Dimeric Alboflavusins with Biaryl Linkages via Regiospecific C–C Bond Coupling

Guo, Zhengyan; Li, Pengwei; Chen, Guozhu; Li, Chao; Cao, Zhenju; Zhang, Yuwei; Ren, Jinwei; Xiang, Hua; Lin, Shuangjun; Ju, Jianhua; Chen, Yihua

doi:10.1021/jacs.8b10136

Cited by 31 publications

(25 citation statements)

References 38 publications

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“…The results revealed that the introduction of exogenous RpsL (P91S) was key to the activation of 3 and 4. Next, the biological activities of 3 and 4 were assayed, 37 with daptomycin as a control (Table 1). Both compounds exhibited the capabilities of killing tested Gram-positive bacteria and fungal pathogens but not Gram-negative bacteria.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A Versatile Transcription–Translation in One Approach for Activation of Cryptic Biosynthetic Gene Clusters

et al. 2020

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The ever-growing drug resistance problem worldwide highlights the urgency to discover and develop new drugs. Microbial natural products are a prolific source of drugs. Genome sequencing has revealed a tremendous amount of uncharacterized natural product biosynthetic gene clusters (BGCs) encoded within microbial genomes, most of which are cryptic or express at very low levels under standard culture conditions. Therefore, developing effective strategies to awaken these cryptic BGCs is of great interest for natural product discovery. In this study, we designed and validated a Transcription− Translation in One (TTO) approach for activation of cryptic BGCs. This approach aims to alter the metabolite profiles of target strains by directly overexpressing exogenous rpsL (encoding ribosomal protein S12) and rpoB (encoding RNA polymerase β subunit) genes containing beneficial mutations for natural product production using a plug-and-play plasmid system. As a result, this approach bypasses the tedious screening work and overcomes the false positive problem in the traditional ribosome engineering approach. In this work, the TTO approach was successfully applied to activating cryptic BGCs in three Streptomyces strains, leading to the discovery of two aromatic polyketide antibiotics, piloquinone and homopiloquinone. We further identified a single BGC responsible for the biosynthesis of both piloquinone and homopiloquinone, which features an unusual starter unit incorporation step. This powerful strategy can be further exploited for BGC activation in strains even beyond streptomycetes, thus facilitating natural product discovery research in the future.

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Section: ■ Results and Discussionmentioning

confidence: 99%

A Versatile Transcription–Translation in One Approach for Activation of Cryptic Biosynthetic Gene Clusters

et al. 2020

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“…Alboflavusin is an analogue of the dimeric non-ribosomal peptide (NRP) anti-tumor agent and apoptosis inducing agents, himastatin and chloptosin. 75 Though less common so far, 5-chlorotryptophans may also be seen as motifs in natural products. Examples include the antibiotic pyrroindomycin B 27; the first step in the biosynthesis of this compound is the generation of 5-chlorotryptophan by PyrH.…”

Section: Mechanisms For Biocatalytic Halogenationmentioning

confidence: 99%

“…Alboflavusin is an analogue of the dimeric non-ribosomal peptide (NRP) anti-tumor agent and apoptosis inducing agents, himastatin and chloptosin. 75 …”

Section: Introductionmentioning

confidence: 99%

Halogenases: a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation

et al. 2021

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“…313 . In 2018, Guo et al designed and synthesized two dimeric AFNs (di‐AFNs) with biaryl linkages via C–C bond coupling (Figure ). As anticipated, the di‐AFNs exhibited much better antitumor and antibacterial activities than their monomers (10‐100‐fold improvement of antibiotic activities).…”

Section: Strategies To Develop Cyclic Peptides Into Therapeutic Agentsmentioning

confidence: 99%

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Jing

Jin

2019

Medicinal Research Reviews

120

130

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As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide‐based drug candidates, drawing upon series of examples to illustrate each strategy.

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Design and Biosynthesis of Dimeric Alboflavusins with Biaryl Linkages via Regiospecific C–C Bond Coupling

Cited by 31 publications

References 38 publications

A Versatile Transcription–Translation in One Approach for Activation of Cryptic Biosynthetic Gene Clusters

A Versatile Transcription–Translation in One Approach for Activation of Cryptic Biosynthetic Gene Clusters

Halogenases: a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

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