One of the most advanced projects is the development of new inhibitors of the interaction between the Mycobacterium tuberculosis (Mtb) thioredoxin reductase (TrxR) and its substrate thioredoxin. The thioredoxin reductase is a validated drug target, since it is essential for thiol redox homeostasis and maintaining infection in mice.1 Genetic inactivation of Mtb TrxR in vivo eradicates Mtb during acute and chronic mouse infections. Most importantly, the mycobacterial TrxR shows a completely different structure and reaction mechanism in comparison to the human TrxR, which makes Mtb TrxR a very good and innovative drug target.

By means of docking into the available mycobacterial TrxR crystal structure, the first inhibitors of the underlying protein-protein interaction were identified.2 Subsequently, the most promising hit was developed into the final candidate using structure-based design and computational permeability optimization.3 This final candidate showed a clear dose-dependent activity on Mtb growth in infected human macrophages, without affecting macrophage viability.

Oliver Koch is currently the coordinator and project leader of a collaboration project in the context of the German Center for Infection Research (DZIF, www.dzif.de) to further develop this compound class. The project partners are Prof. Dr. M. Brönstrup (HZI Braunschweig) and Drs. Norbert Reiling and Christoph Hölscher (Research Center Borstel). It is planned to develop the most promising compounds into a candidate structure that shows its activity in a mouse model after oral administration. The current lead compound allows a multi-objective optimization with respect to absorption, distribution, metabolism, extinction, and toxicity (ADME-Tox) parameters, and bioactivity aspects. This will be performed using structure-based design and in-silico optimization (by Oliver Koch). The necessary X-ray crystallography and biochemical characterisation are performed by Friederike Füsser and Ann-Kathrin Prinz  (Team) in close collaboration with the Kümmel group (Prof. Dr. D. Kümmel).

References

  1. Lin, K., O'Brien, K.M., Trujillo, C., Wang, R., Wallach, J.B., Schnappinger, D., Ehrt, S. Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense. PLoS Pathog. 2016, 12, e1005675.
  2. Koch, O.*, Jäger, T., Heller, K., Khandavalli, P.C., Pretzel, J., Becker, K., Flohé, L., Selzer, P.M.* Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints. J. Med. Chem. 2013, 56, 4849-4859. http://dx.doi.org/10.1021/jm3015734
  3. Koch, O., Bering, L. Mycobacterium tuberculosis Thioredoxin Reductase Inhibitor as Antituberculosis Drug. EP 17 179 568.5 filed 04.07.2017 & PCT/EP2018/066768 filed 22.6.2018