Assessing potential inhibitors against the NS2B-NS3 dengue virus protease

We have worked on the dengue virus protease for many years (e.g. 1-3). Most structures determined by X-ray crystallography turned out to be crystallisation artifacts and crystallisation with inhibitors is almost impossible. In a new collaboration with an international consortium of researchers, we will use NMR spectroscopy in solution to identify the binding mode of lead compounds against the NS2B-NS3 protease. This structural information will provide the essential guide for making improved inhibitors.

The project includes:

  • cell-free and in vivo synthesis of the protease with 15N-labelled amino acids
  • tagging with paramagnetic lanthanide tags
  • NMR spectroscopy

Publications

  • (1) de la Cruz, L., Nguyen, T. H. D., Ozawa, K., Shin, J., Graham, B., Huber, T. and Otting, G. (2011) Binding of low-molecular weight inhibitors promotes large conformational changes in the dengue virus NS2B-NS3 protease: fold analysis by pseudocontact shifts. J. Am. Chem. Soc. 133, 19205-19215.
  • (2) de la Cruz, L., Chen, W.-N., Graham, B. and Otting, G. (2014) Binding mode of the activity-modulating C-terminal segment of NS2B to NS3 in the dengue virus NS2B-NS3 protease. FEBS J. 281, 1517-1533.
  • (3) Chen, W.-N., Loscha, K. V., Nitsche, C., Graham, B. and Otting, G. (2014) The dengue virus NS2B-NS3 protease retains the closed conformation in the complex with BPTI. FEBS Lett., in press.

Partnerships

  • Novartis Institute for Tropical Diseases, Singapore
  • Deutsches Krebsforschungszentrum, Heidelberg

Image gallery

Updated:  20 September 2017/Responsible Officer:  Director, RSC/Page Contact:  Web Admin, RSC