First Hospital of Shanxi Medical University, Taiyuan, China.
Center for Food and Drug Evaluation & Inspection of Henan, Zhengzhou, China.
Ann Med. 2022 Dec;54(1):1590-1600. doi: 10.1080/07853890.2022.2081869.
Proteinśprotein interaction (PPI) between lens epithelium-derived growth factor (LEDGF/p75) and human immunodeficiency virus (HIV) integrase (IN) becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. In this study, a panel of 99 structurally related flavonoids were was tested, concerning their ability to inhibit IN-LEDGF/p75 interaction, using a homogeneous time time-resolved fluorescence (HTRF) assay. From the obtained results, it was possible to observe that the flavonoid with hydroxyl group in C3-, C4-, C5- and C7-position on the A-ring, C4'- and C5'-position of the B-ring, a carbonyl group of the C-ring, was more active against IN-LEDGF/p75 interaction, through competitive inhibition. Moreover, the binding modes of representative compounds, including myricetin, luteolin, dihydrorobinetin, naringenin, epicatechin, genistein and helichrysetin, were analyzedanalysed by molecular docking. Biolayer interferometry assay confirmed that these representative compounds disrupted the PPI by binding to IN with KD values ranging from 1.0 to 3.6 µM. This study presents the first to quantitative comparation of the effect of flavonoids with different structural subclasses on IN-LEDGF/p75 interaction. Our findings provide new insights into the development of inhibitors targeting IN-LEDGF/p75 interaction using flavonoids. Key MessagesHIV-1 integrase (IN)-LEDGF/p75 interaction is an attractive target for antiviral drug development.For the first time, the structure-activity relationship of flavonoids belonging to seven flavonoidic subclasses on IN-LEDGF/p75 interaction was determined.This study comprehends an HTRF-based screening system, biolayer interferometry and an in silico molecular docking analysis.
蛋白质-蛋白质相互作用（PPI）在晶状体上皮衍生生长因子（LEDGF/p75）和人类免疫缺陷病毒（HIV）整合酶（IN）之间，成为抗 HIV 药物开发的一个有吸引力的靶点。通过小分子阻断这种相互作用可能会抑制 HIV-1 的复制。在这项研究中，使用均相时间分辨荧光（HTRF）测定法，测试了一组 99 种结构相关的黄酮类化合物，以评估它们抑制 IN-LEDGF/p75 相互作用的能力。从获得的结果中，可以观察到 A 环上 C3、C4、C5 和 C7 位、B 环上 C4′和 C5′位、C 环上羰基有羟基的黄酮类化合物，对 IN-LEDGF/p75 相互作用的抑制作用更强，这是通过竞争性抑制实现的。此外，通过分子对接分析了代表性化合物，包括杨梅素、木犀草素、二氢山奈酚、柚皮素、表儿茶素、染料木黄酮和芹黄素，代表化合物的结合模式。生物层干涉测定法（Biolayer interferometry assay）证实，这些代表性化合物通过与 IN 结合来破坏 PPI，KD 值范围为 1.0 至 3.6μM。这项研究首次对不同结构亚类的黄酮类化合物对 IN-LEDGF/p75 相互作用的影响进行了定量比较。我们的研究结果为利用黄酮类化合物开发靶向 IN-LEDGF/p75 相互作用的抑制剂提供了新的见解。关键信息HIV-1 整合酶（IN）-LEDGF/p75 相互作用是抗病毒药物开发的一个有吸引力的靶点。首次确定了属于七种黄酮类亚类的黄酮类化合物对 IN-LEDGF/p75 相互作用的构效关系。本研究包括基于 HTRF 的筛选系统、生物层干涉测定法和计算机分子对接分析。
