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Self-assembled small molecule natural product gel for drug delivery: a breakthrough in new application of small molecule natural products.

ABSTRACT: Natural products, as a gift of nature to humanity, have long been used as drugs or pharmacological actives to help people cure various diseases. Yet we still know comparatively little about their ability to be materials. In recent years, some small molecule natural products isolated from traditional Chinese medicines have been found to have new features, namely, self-assembly to form gels (i.e., natural product gels, NPG). However, the application development of these natural products is seriously lacking, which greatly weakens their practical value and delays the maturity of the field. Here, a series of self-assembled triterpenoid natural products are used as materials (gel scaffolds) to construct drug delivery systems. Surprisingly, these NPG not only exhibit the excellent self-healing, controlled gelation, good safety and sustained release, but also achieve synergistic treatment of tumors through bioactive natural products. Compared with non-bioactive gel scaffolds, NPG scaffolds show great advantages in tumor therapy, including optimal tumor inhibition, preferable health, better body recovery, stronger immune function, less toxic side effects and longer survival. The successful construction of NPG scaffolds not only takes full advantage of the self-assembled natural products, but also takes an important step in the development of new applications for natural products.

SUBMITTER: Zhi K

PROVIDER: S-EPMC7280148 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Self-assembled small molecule natural product gel for drug delivery: a breakthrough in new application of small molecule natural products.

Zhi Kangkang K Wang Jiacheng J Zhao Haitian H Yang Xin X

Acta pharmaceutica Sinica. B 20191006 5

Natural products, as a gift of nature to humanity, have long been used as drugs or pharmacological actives to help people cure various diseases. Yet we still know comparatively little about their ability to be materials. In recent years, some small molecule natural products isolated from traditional Chinese medicines have been found to have new features, namely, self-assembly to form gels (<i>i.e</i>., natural product gels, NPG). However, the application development of these natural products is ...[more]

PMID: 32528837

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Project description:N6-Methyladenosine (m6A) is the most prevalent mRNA modification in mammalian cells that is mainly catalyzed by the methyltransferase complex of methyltransferase-like 3 and methyltransferase-like 14 (METTL3-METTL14). Many lines of evidence suggest that METTL3 plays important roles in several diseases such as cancers and viral infection. In the present study, 1,042 natural products from commercially available sources were chosen to establish a screening library, and docking-based high-throughput screening was performed to discover potential METTL3 inhibitors. The selected compounds were then further validated by an in vitro methyltransferase inhibition assay in which m6A content was determined by LC-MS/MS. A cellular assay of the inhibition of m6A methylation was performed to determine the METTL3 inhibitory activity of the selected compound. CCK-8 assay was applied to evaluate the effects of the selected compound on tumor cell viability. Additionally, binding mode analysis, molecular dynamics (MD) simulation, and binding free energy analysis were performed to study the process and characteristics of inhibitor binding. Finally, quercetin was identified as a METTL3 inhibitor with an IC50 value of 2.73 μM. The cellular assay of m6A methylation inhibition showed that quercetin decreased m6A level in a dose-dependent manner in MIA PaCa-2 pancreatic cancer cells. CCK-8 assay showed quercetin efficiently inhibited the proliferation of MIA PaCa-2 and Huh7 tumor cells, with IC50 values 73.51 ± 11.22 μM and 99.97 ± 7.03 μM, respectively. Molecular docking studies revealed that quercetin filled the pocket of the adenosine moiety of SAM but not the pocket of the SAM methionine in the METTL3 protein, and hydrogen bonds, hydrophobic interactions, and pi-stacking were formed. The values of the root mean square deviation (RMSD), the root mean square fluctuations (RMSF), and binding free energy suggested that quercetin can efficiently bind to the pocket of the METTL3 protein and form a stable protein-ligand complex. The present study is the first to identify METTL3 inhibitors from natural products, thus providing a basis for subsequent research and facilitating the development of METTL3-targeting drugs for diseases.

Dataset Information

Self-assembled small molecule natural product gel for drug delivery: a breakthrough in new application of small molecule natural products.

Publications

Self-assembled small molecule natural product gel for drug delivery: a breakthrough in new application of small molecule natural products.

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