2023-08-08 ジョージア大学 (UGA)
◆この発見は、ウイルスに感染した細胞を特定して排除する新しい方法を提供する可能性があります。これにより、従来の抗ウイルス薬とは異なるアプローチで感染症を制御できるかもしれません。しかし、まだ実際の治療法として使用できる段階には至っていないため、今後の研究と臨床試験が必要です。
<関連情報>
- https://news.uga.edu/new-molecule-could-treat-shingles-herpes/
- https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00545
水痘帯状疱疹ウイルス(VZV)に対するβ-l-5-((E)-2-ブロモビニル)-1-((2S,4S)-2-(ヒドロキシメチル)-1,3-(ジオキソラン-4-イル)ウラシル(l-BHDU)開発のためのプロドラッグ戦略) Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV)
Uma S. Singh, Ananda K. Konreddy, Yugandhar Kothapalli, Dongmei Liu, Megan G. Lloyd, Vidya Annavarapu, Catherine A. White, Michael. G. Bartlett, Jennifer F. Moffat, and Chung K. Chu
Journal Medicinal Chemistry Published:May 4, 2023
DOI:https://doi.org/10.1021/acs.jmedchem.3c00545
Abstract
Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified β-l-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU, 1), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous l-BHDU prodrugs: amino acid esters (14–26), phosphoramidates (33–34), long-chain lipids (ODE-l-BHDU-MP, 38, and HDP-l-BHDU-MP, 39), and phosphate ester prodrugs (POM-l-BHDU-MP, 41, and POC-l-BHDU-MP, 47). The amino acid ester l-BHDU prodrugs (l-phenylalanine, 16, and l-valine, 17) had a potent antiviral activity with EC50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-l-BHDU-MP and POC-l-BHDU-MP had a significant anti-VZV activity with EC50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC50 > 100 μM) was detected. Out of these prodrugs, ODE-l-BHDU-MP (38) and POM-l-BHDU-MP (41) were selected for further evaluation in future studies.
