Lukas Brändli

 

PhD Student

Location:

HCI G-320

Phone:

+41-44-632 2955

e-mail:

Lukas Brändli

Education

1998-2002:

Studies in chemistry at ETH Zürich

2002:

Diploma thesis with Prof. F. Diederich, ETH Zürich

2003:

Internship at Hoffmann-La Roche in Basel

since 2003:

PhD with Prof. F. Diederich at ETH Zurich

Structure-based Design and Synthesis of Small-molecule Inhibitors of the Dimerization of Varicella Zoster Thymidine Kinase (VZV TK)

Varicella Zoster Thymidin Kinase and its hot spot.

Varicella Zoster Virus Thymidin Kinase (VZV TK) belongs to the family of the nucleotide monophosphate (NMP) kinases and contains the classical mononucleotide binding fold. VZV TK is active in infected cells in the phosphorylation of nucleoside antiviral drugs, such as acyclovir, that inhibit in the triphosphate form VZV DNA polymerases. On the other hand, VZV TK could itself be a target in the fight of VZV infections (shingles) in immuno-compromized hosts. The kinase plays an important role in the reactivation of the virus in nerve cells.

The side chains of three amino acids, Leu276, Trp277, and Trp279 are essential for the dimerization of VZV TK and thus assumed to form the hot spot. These three amino acids with the relative positions i, i + 1, i + 3 are located at the terminal point of an alpha-helix, which is tilted out of the plane of the interface. The region, where the three residues interact with the other protein subunit, creates a cavity which serves as binding pocket for the designed ligands.