Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, IBUB, Universitat de Barcelona, 08028 Barcelona, Spain.
Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain.
Molecules. 2023 Oct 11;28(20):7031. doi: 10.3390/molecules28207031.
Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE-Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE-Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE-Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.
人类免疫缺陷病毒 1 型（HIV-1）仍然是导致全球疾病负担的主要原因之一，需要新型具有替代机制的抗逆转录病毒药物来治愈这种感染。在这里，我们描述了一种探索性尝试，旨在优化苯并[c]氟仑的抗逆转录病毒特性，苯并[c]氟仑是一种先前报道具有强烈抗 HIV 活性的细胞抑制剂，可能基于对病毒转录和 Rev 介导的病毒 RNA 输出的抑制作用。在获得了六个旨在修饰母体分子苯并[c]氟仑酮系统的类似物后，我们一起研究了它们的抗逆转录病毒和毒性特性，以及它们识别病毒 RNA 的 Rev 识别元件（RRE）和抑制 RRE-Rev 相互作用的能力。结果表明，苯并[c]和环戊酮部分对于强烈的 RRE-Rev 靶标结合和抗逆转录病毒活性都是必需的，并揭示了这些部分对 RRE 亲和力、RRE-Rev 抑制、抗病毒作用和细胞毒性的相对影响。这些数据提供了对苯并[c]氟仑酮支架的生物学特性的深入了解，并有助于基于 Rev 功能抑制设计新型抗 HIV 药物。
