Natural Product Modulators of Protein-Protein Interactions: A Comprehensive Review.

IF 2.9 3区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Phytochemical Analysis Pub Date : 2026-04-01 Epub Date: 2026-02-12 DOI:10.1002/pca.70054

Emadeldin M Kamel, Ahmed A Allam, Hassan A Rudayni, Faris F Aba Alkhayl, Noha A Ahmed, Al Mokhtar Lamsabhi

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引用次数: 0

Abstract

Introduction: Natural products offer structurally diverse small molecules that modulate protein-protein interactions (PPIs) by disrupting pathogenic complexes or stabilizing beneficial ones, expanding therapeutic opportunities beyond classical enzyme inhibition.

Objective: This review synthesizes natural product PPI modulators, emphasizing target coverage, mechanisms of action, reported potency/affinity, structural evidence, and functional outcomes in cellular or organismal models.

Methods: We curated published examples of natural products acting as direct PPI inhibitors or indirect modulators and organized them by (i) functional PPI categories-oncogenic complexes (MDM2-p53, BCL-2 family, IAP-caspase), signaling assemblies (Wnt/β-catenin, 14-3-3/adaptor complexes), chaperone/co-chaperone systems (Hsp90 and partners), and immunophilin-mediated interactions (calcineurin-NFAT, mTOR complexes)-and (ii) mechanistic class, including competitive interface blockade, allosteric modulation, covalent modification of one partner, and stabilization via molecular glue or ternary-complex formation. For each class, we summarize representative scaffolds and report binding affinities or IC50/Ki values and structural data when available.

Results: Natural products span multiple modes of PPI control and highlight tractable intervention points across diverse proteins. Representative examples include chlorofusin, a fungal metabolite that disrupts p53-MDM2 (IC₅₀ ~ 4.6 μM); (-)-gossypol, a plant polyphenol acting as a BH3 mimetic that binds BCL-xL (K_i ~ 0.5 μM); celastrol, a covalent triterpenoid that impairs the Hsp90-Cdc37 complex; and cyclosporin A, FK506, and rapamycin, which form ternary complexes to reprogram immunophilin PPIs.

Conclusion: Collectively, these modulators demonstrate PPI druggability and provide chemical probes and lead scaffolds for therapeutic development in cancer, neurodegeneration, infectious disease, and immune disorders.

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蛋白质相互作用的天然产物调节剂：综述。

天然产物提供结构多样的小分子，通过破坏致病性复合物或稳定有益复合物来调节蛋白质-蛋白质相互作用（PPIs），扩大了经典酶抑制之外的治疗机会。目的：本文综述了天然产品PPI调节剂的合成，强调了靶点覆盖、作用机制、已报道的效价/亲和力、结构证据和细胞或组织模型的功能结果。方法:我们整理了已发表的天然产物作为直接PPI抑制剂或间接调节剂的例子，并通过(i)功能性PPI分类——致癌复合物（MDM2-p53， BCL-2家族，IAP-caspase），信号组装（Wnt/β-catenin， 14-3-3/适配器复合物），伴侣/共伴侣系统（Hsp90和伙伴），亲免疫蛋白介导的相互作用（钙调磷酸酶- nfat， mTOR复合物）和（ii）机制分类，包括竞争性界面阻断，变构调节，通过分子胶或三元络合物形成的共价修饰和稳定。对于每一类，我们总结了具有代表性的支架，并在可用的情况下报告结合亲和力或IC50/Ki值和结构数据。结果：天然产物跨越多种PPI控制模式，并在多种蛋白质中突出可处理的干预点。代表性的例子包括氯藻素，一种破坏p53-MDM2的真菌代谢物（IC50 ~ 4.6 μM）；（-）-棉酚，一种植物多酚，作为BH3模拟物，结合BCL-xL (Ki ~ 0.5 μM)；雷公藤红素，一种共价三萜，损害Hsp90-Cdc37复合物；以及环孢素A、FK506和雷帕霉素，它们形成三元复合物来重编程PPIs中的亲免疫蛋白。结论：总的来说，这些调节剂显示出PPI的药物性，并为癌症、神经退行性疾病、传染病和免疫疾病的治疗发展提供了化学探针和铅支架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytochemical Analysis 生物-分析化学

CiteScore

6.00

自引率

6.10%

发文量

审稿时长

1.7 months

期刊介绍： Phytochemical Analysis is devoted to the publication of original articles concerning the development, improvement, validation and/or extension of application of analytical methodology in the plant sciences. The spectrum of coverage is broad, encompassing methods and techniques relevant to the detection (including bio-screening), extraction, separation, purification, identification and quantification of compounds in plant biochemistry, plant cellular and molecular biology, plant biotechnology, the food sciences, agriculture and horticulture. The Journal publishes papers describing significant novelty in the analysis of whole plants (including algae), plant cells, tissues and organs, plant-derived extracts and plant products (including those which have been partially or completely refined for use in the food, agrochemical, pharmaceutical and related industries). All forms of physical, chemical, biochemical, spectroscopic, radiometric, electrometric, chromatographic, metabolomic and chemometric investigations of plant products (monomeric species as well as polymeric molecules such as nucleic acids, proteins, lipids and carbohydrates) are included within the remit of the Journal. Papers dealing with novel methods relating to areas such as data handling/ data mining in plant sciences will also be welcomed.