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Archive > Volume 17 Issue 2 > 2025,17(2):235-245. DOI:https://doi.org/10.1016/j.chmed.2025.01.001 Prev Next

源于天然產(chǎn)物的分子膠研究進(jìn)展：化學(xué)、靶標(biāo)和分子機制

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Research advancements in molecular glues derived from natural product scaffolds: Chemistry, targets, and molecular mechanisms

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    摘要:
    摘要：中藥的作用機制極其復(fù)雜，長期以來人們一直致力于研究不同中藥活性成分對靶點蛋白的直接調(diào)控作用，但是目前的研究結(jié)果尚不足以概括中藥作用的全部復(fù)雜機制。近年來，分子膠（Molecular glues）理論的出現(xiàn)為詮釋中藥復(fù)雜作用機制提供了一個新的思路。分子膠是一種化學(xué)小分子，可以特異性促進(jìn)不同蛋白質(zhì)之間的相互作用并產(chǎn)生生物學(xué)效應(yīng)。即分子膠的作用特點是在不同的蛋白質(zhì)之間建立聯(lián)系，從而產(chǎn)生化學(xué)分子介導(dǎo)的蛋白質(zhì)鄰近效應(yīng)，觸發(fā)廣泛的生物學(xué)活性。由于天然活性分子是自然界數(shù)十億年進(jìn)化過程中的產(chǎn)物，因此天然活性分子廣泛的結(jié)構(gòu)多樣性使它們成為分子膠的豐富來源，包括聚酮類、萜類、甾體類、木脂素類、有機酸類、生物堿類等。目前，已經(jīng)發(fā)現(xiàn)的天然分子膠包括免疫抑制劑環(huán)孢素A和他克莫司，以及抗癌藥物紫杉醇等。與此同時，新技術(shù)的進(jìn)步正在推動天然產(chǎn)物中新型分子膠的發(fā)現(xiàn)。因此，本文主要總結(jié)了近年來報道的多種天然來源的分子膠，并根據(jù)化學(xué)結(jié)構(gòu)類型對其進(jìn)行了分類。此外，中藥也是天然活性分子的重要來源，因此天然分子膠的發(fā)現(xiàn)有望為中藥作用機制的闡明提供一個全新的視角?？傊疚闹荚跒榇蠹姨峁┮粋€理解天然產(chǎn)物復(fù)雜作用機制的新視角，這也可能會給中醫(yī)藥現(xiàn)代化研究及現(xiàn)代創(chuàng)新藥物的研發(fā)提供新方向。

    Abstract:
    The mechanism of action of traditional Chinese medicine (TCM) remains unclear. Historically, research on TCM has mainly focused on exploring the mechanisms of active components acting on single targets. However, it is insufficient to explain the complex mechanisms by which these active components in TCM treat diseases. In recent years, the emergence of molecular glues (MGs) theory has provided new strategies to address this issue. MGs are small molecules that can promote interactions between proteins at their interface. The characteristic of MGs is to establish connections between diverse protein structures, thereby enabling a chemically-mediated proximity effect that triggers a wide spectrum of biological functions. Natural products are the result of billions of years of evolutionary processes in the natural environment. Thus, the extensive structural diversity of natural products renders them a rich source of MGs, including polyketides, terpenoids, steroids, lignans, organic acids, alkaloids and other classes. Currently, several well-known natural MGs, including the immunosuppressants cyclosporin A (CsA) and tacrolimus (FK506), as well as the anticancer agent taxol, have been incorporated into clinical practice. Meanwhile, the advancement of new technologies is propelling the discovery of novel MGs from natural products. Thus, we primarily summarize a growing variety of MGs from natural origins reported in recent years and categorize them based on the chemical structural types. Moreover, the main sources of TCM are natural products. The discovery of natural MGs promises to provide a new perspective for the elucidation of the molecular mechanism behind the efficiency of TCM. In summary, this review aims to provide insights from the perspective of natural products that could potentially influence TCM and modern drug development.

    關(guān)鍵詞:
    化學(xué)誘導(dǎo)鄰近效應(yīng);藥物開發(fā);分子膠;天然產(chǎn)物;蛋白質(zhì)降解;蛋白質(zhì)-蛋白質(zhì)相互作用

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    Project Supported:
    The study was financially supported by Jinan New 20 Policies for Higher Education Funding (No. 202228048), Natural Science Foundation of Shandong Province (Joint Fundation for Innovation and Development) (No. ZR2022LZY021), the Special Fund for ‘‘Tian-Chi Talent Introduction Program”, and the Special Fund for Taishan Scholars Project in Shandong Province (No. tstp20230633).

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