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

• Published in: Journal of medicinal chemistry Vol. 53; no. 10; pp. 3899 - 3906
• Main Authors: Cheltsov, Anton V, Aoyagi, Mika, Aleshin, Alexander, Yu, Eric Chi-Wang, Gilliland, Taylor, Zhai, Dayong, Bobkov, Andrey A, Reed, John C, Liddington, Robert C, Abagyan, Ruben
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.05.2010
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Apoptosis Regulatory Proteins - chemistry; Bcl-2-Like Protein 11; Binding Sites; Calorimetry, Differential Scanning; Cell Line; Databases, Factual; Humans; Ligands; Membrane Proteins - chemistry; Models, Molecular; Mutation; Peptide Fragments - chemistry; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Thermodynamics; Ultracentrifugation; Vaccinia virus - drug effects; Vaccinia virus - growth & development; Viral Proteins - antagonists & inhibitors; Viral Proteins - genetics; Virulence Factors - antagonists & inhibitors; Virulence Factors - genetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901446n

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.