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

Abstract

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 sub-micromolar (600 nM) N1L antagonists, belonging to the family of polyphenols. Their affinity is comparable to that of the BH3 peptides (70 nM ÷ 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.

Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters

“…xxxv Asymmetric arylation of requisite aldehyde 55 xxxvi and subsequent alkylation of the alcohol furnished desired heterocyclic substrate 56 in 90% ee (Scheme 12). The cross-coupling reaction was found to proceed in good yield and excellent stereospecificity to give 57 , which was further elaborated over 3 steps to produce 58 , an H 1 antihistamine shown to have anti-insomnia properties.…”

Specific Small Molecule Inhibitors of Skp2-Mediated p27 Degradation

“…Interrogating receptor-ligand atomic contacts and using chemical similarity searches identifies more diverse and/or potent inhibitors (Cheltsov, et al, 2010; Wang, et al, 2009). Thus, a blueprint or pharmacophore of the entire Skp2 ligase inhibitor class is preliminary visualized, which may guide the rational synthesis of derivatives of C1, C2, C16, and C20 during future preclinical lead optimization stages.…”

Zinc‐Catalyzed Synthesis of Functionalized Furans and Triarylmethanes from Enynones and Alcohols or Azoles: Dual XH Bond Activation by Zinc

“…Since these compounds are relevant in different areas such as medicinal chemistry or materials science, [11,12] we subsequently optimized the reaction conditions and evaluated the scope. In this regard, we did not observe the formation of the desired furfuryl amines when piperidine or tosylamide were reacted with 1 a under various reaction conditions.…”