State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R & D, Guizhou Medical University, Guiyang 550025, China.
School of Medicine and Health Management, Guizhou Medical University, Guiyang 550025, China.
J Agric Food Chem. 2024 Oct 2;72(39):21877-21891. doi: 10.1021/acs.jafc.4c03946. Epub 2024 Sep 18.
-pregnane C steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of -pregnane C steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural -pregnane C steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, , , and with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of and . Computational simulations indicated that displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (Δ = -56.2 kcal/mol) compared with Ribavirin (Δ = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.
孕烷 C 甾体对烟草花叶病毒（TMV）表现出很高的抗病毒活性。然而，孕烷 C 甾体的结构修饰及其修饰化合物的构效关系（SAR）尚未得到评估。因此，本研究探讨了天然孕烷 C 甾体原始骨架的变化如何影响其抗病毒活性。首次设计并合成了一系列羽扇豆烷 C 和 A 衍生物，并对其抗 TMV 活性进行了评价。生物测定结果表明，大多数新设计的衍生物表现出良好到优异的抗病毒活性；其中， 、 、 和 具有比宁南霉素更高的抗病毒活性，是新的抗病毒候选物。逆转录-聚合酶链反应和 Western 印迹分析显示，这些衍生物降低了 TMV 外壳蛋白（TMV-CP）基因转录和 TMV-CP 蛋白表达水平，证实了它们的抗病毒活性。这些化合物还下调了 和 的表达。计算模拟表明， 与 TMV 外壳蛋白表现出强烈的范德华能和静电相互作用，提供了比利巴韦林（Δ=-47.6 kcal/mol）更低的结合能（Δ=-56.2 kcal/mol）。还评估了这些化合物的 SAR，首次证明 C-3 和 C-5/C-6 和 C-13/C-18 双键的取代对于保持高抗 TMV 活性至关重要。
