Dataset Information

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

ABSTRACT: Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.

SUBMITTER: Leng L

PROVIDER: S-EPMC10879537 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

Leng Liang L Xu Zhichao Z Hong Bixia B Zhao Binbin B Tian Ya Y Wang Can C Yang Lulu L Zou Zhongmei Z Li Lingyu L Liu Ke K Peng Wanjun W Liu Jiangning J An Zhoujie Z Wang Yalin Y Duan Baozhong B Hu Zhigang Z Zheng Chuan C Zhang Sanyin S Li Xiaodong X Li Maochen M Liu Zhaoyu Z Bi Zenghao Z He Tianxing T Liu Baimei B Fan Huahao H Song Chi C Tong Yigang Y Chen Shilin S

Nature communications 20240220 1

Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with on ...[more]

PMID: 38378731

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Project description:IntroductionStephania longa, a medicinal plant renowned for producing cepharanthine, has gained significance due to the compound's notable antiviral properties against SARS-CoV-2. However, a comprehensive genetic understanding of S. longa has been lacking. This study aimed to develop a high-quality, chromosome-level genome assembly to uncover the genetic intricacies and evolutionary narrative of this species. By integrating genomic data with metabolomic and transcriptomic analyses, we sought to identify key genes involved in cepharanthine biosynthesis.MethodsWe employed a multi-faceted approach comprising genome assembly, phylogenetic analysis, gene family dynamics investigation, metabolomic profiling, and gene expression analysis across various tissues of S. longa. This integrated strategy enabled the identification of key genes involved in cepharanthine biosynthesis and elucidated the species' evolutionary history.ResultsOur phylogenetic analysis clarified the placement of the genus Stephania within the Ranunculales order and revealed its notably high mutation rate. We identified gene family expansions and signs of positive selection likely contributing to Stephania's unique metabolic capabilities. Metabolomic profiling uncovered complex regulatory mechanisms orchestrating the biosynthesis and distribution of cepharanthine and related metabolites. Through the integration of genomic, transcriptomic, and metabolomic data, we identified genes with expression patterns and evolutionary trajectories suggesting pivotal roles in cepharanthine biosynthesis, including those involved in crucial biosynthetic steps.DiscussionThis comprehensive study, integrating genomic, metabolomic, and transcriptomic approaches, provides valuable insights into S. longa's biosynthetic potential. It not only enhances our understanding of the species but also establishes a foundation for future investigations into the biosynthesis and therapeutic exploitation of cepharanthine and related alkaloids.

Project description:BACKGROUND:Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS:Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS:Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS:This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Dataset Information

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

Publications

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

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