Department of Chemistry, University of Rochester, Rochester, NY 14642, USA.
Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY 14642, USA.
Org Biomol Chem. 2022 Jan 19;20(3):606-612. doi: 10.1039/d1ob01976g.
As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines (DKPs), common substructures in natural products and protein-targeting therapeutic agents, could serve as effective scaffolds for targeting RNA. To confirm this hypothesis, we designed and synthesized two analogs, one incorporating a DKP and one not, of compounds previously demonstrated to bind an RNA critical to the life cycle of HIV-1 with high affinity and specificity. Prior to compound synthesis, calculations employing density functional methods and molecular mechanics conformational searches were used to confirm that the DKP could present functionality in a similar (albeit not identical) orientation to the non DKP-containing compound. We found that both the DKP-containing and parent compound had similar affinities to the target RNA as measured by surface plasmon resonance (SPR). Both compounds were found to have modest but equal anti-HIV activity. These results establish the feasibility of using DKPs to target RNA.
随着 RNA 作为治疗靶点的重要性日益受到重视，对于能够结合 RNA 的新型化学型的需求变得越来越重要。我们假设二酮哌嗪（DKP），在天然产物和靶向蛋白的治疗药物中常见的亚结构，可用作靶向 RNA 的有效支架。为了验证这一假设，我们设计并合成了两种类似物，一种是以前证明与 HIV-1 生命周期中至关重要的 RNA 具有高亲和力和特异性的化合物的 DKP 类似物，另一种则没有 DKP。在化合物合成之前，使用密度泛函方法和分子力学构象搜索进行计算，以确认 DKP 可以以类似于（尽管不完全相同）的方向呈现与不含 DKP 的化合物相同的功能。我们发现，通过表面等离子体共振（SPR）测量，含 DKP 的化合物和母体化合物与靶 RNA 的亲和力相似。这两种化合物都被发现具有适度但相等的抗 HIV 活性。这些结果确立了使用 DKP 靶向 RNA 的可行性。
