Dr Oliver Koch, Technical University of Dortmund; Luis Bering, Technical University of Dortmund
The resurgence of tuberculosis, caused primarily by Mycobacterium tuberculosis (Mtb), and the appearance of multi‐drug and extensively drug resistant Mtb strains strengthen the need for new drugs with alternative modes of action.
The interaction between the mycobacterial thioredoxin reductase (TrxR) and its substrate thioredoxin (Trx) is a promising new drug target for the treatment of tuberculosis, since Mtb lacks the common glutathione system and the mycobacterial TrxR shows a substantial difference in sequence, mechanism and structure to human TrxRs. It was shown that TrxR is essential for thiol redox homeostasis and genetic inactivation in vivo eradicates Mtb during acute and chronic mouse infections (Lin et al., PLoS Pathog. 2016). In order to further improve the bioactivity of promising compounds, researchers of the TU Dortmund University have focused on optimizing the physico-chemical properties that are important for permeability, since M. tuberculosis shows an unusual thick and impermeable cell wall.
The technology is offered for licensing and further therapeutic development.
The researchers are preparing the further development towards mice studies to confirm in vivo efficacy, as well as ADME Tox studies.
European priority application has been filed on July 4, 2017.
Koch, O., et al. (2013) Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints J. Med. Chem. 56(12): 4849-59.
Compounds with improved physicochemical properties with regard to increased permeability and bioactivity were designed. The most promising compound (BE‐068) was also tested on infected human macrophages and showed a clear dose‐dependent activity on mycobacterial growth (upper graph), without affecting macrophage viability (lower graph).