Vaccinia Virus Virulence Factor N1L is a Novel Promising Target for Antiviral Therapeutic Intervention

详细信息    查看全文

• 作者：Anton V. Cheltsov ; Mika Aoyagi ; Alexander Aleshin ; Eric Chi-Wang Yu ; Taylor Gilliland ; Dayong Zhai ; Andrey A. Bobkov ; John C. Reed ; Robert C. Liddington ; Ruben Abagyan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：3899-3906
• 全文大小：878K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

The 14 kDa homodimeric N1L protein is a potent vaccinia and variola (smallpox) virulence factor. It is not essential for viral replication, but it causes a strong attenuation of viral production in culture when deleted. The N1L protein is predicted to contain the BH3-like binding domain characteristic of Bcl-2 family proteins, and it is able to bind the BH3 peptides. Its overexpression has been reported to prevent infected cells from committing apoptosis. Therefore, interfering with the N1L apoptotic blockade may be a legitimate therapeutic strategy affecting the viral growth. By using in silico ligand docking and an array of in vitro assays, we have identified submicromolar (600 nM) N1L antagonists belonging to the family of polyphenols. Their affinity is comparable to that of the BH3 peptides (70−1000 nM). We have also identified the natural polyphenol resveratrol as a moderate N1L inhibitor. Finally, we show that our ligands efficiently inhibit growth of vaccinia virus.