WP 2: DESIGN AND SYNTHESIS OF INHIBITORS OF THE MEP PATHWAY

The drug-discovery projects will exploit established as well as innovative hit-identification strategies. Structure- and fragment-based design, classical structure-activity relationship (SAR) study, dynamic combinatorial chemistry and kinetic target-guided synthesis will be used to identify novel, selective and potent inhibitors of the MEP pathway enzymes.

The binding mode of the most promising hits will be determined by saturation-transfer difference (STD)-NMR, site-directed mutagenesis and co-crystal structures, thanks to the close cooperation with WP1. The compounds obtained will be tested in cellulo and demonstrated target engagement using the collaboration with WP 3.

The students will be trained in the design and synthesis of novel inhibitors and in the multiparameter optimization process to achieve lead compounds.

ESR 4: Design and synthesis of inhibitors of the enzymes DXS and IspD

The hit compounds identified by ESR 3, ESR 8 and ESR 9 will be the starting point for a fragment growing approach. The optimised compound should fullfil the parameter of a lead compound that can be used by the colleagues of WP 3 for in vivo tests.

Complementary to fragment screening and structure-based virtual screening, ESR 4 will follow also more innovative and novel hit identification strategies, such as dynamic combinatorial chemistry (DCC) and kinetic target-guided synthesis (KTGS).

Supervisor: Prof. Anna K. H. Hirsch

Secondments: University of Bergen (Uib) / Academia

OmicScouts / Industry

ESR 5: Synthesis of prodrugs of DXR inhibitors

Fosmidomycin is a potent inhibitor of DXR enzyme, active against P. falciparum, but devoid of antibacterial activity. The aim of the project is the design of prodrug compounds by converting the fosmidomycin and his analogues, into hydrophobic phosphonate compounds. The latter ones should have the ability to cross the gram-negative barrier.

The target engagement of these newly synthesised compounds will be tested by ESR 12 in a chemical proteomics approach.

Supervisor: Prof. Serge Van Calenbergh

Secondments: Rijksuniversiteit Groningen (RUG) / Academia

Specs / Industry

ESR 6: Optimisation of inhibitors of the enzymes IspE and IspF

Inhibitors of IspE/IspF will be validated and subsequently optimised in hit-to-lead optimisation programmes according to the standard of the pharmaceutical industry. Aiming to obtain high-quality compound, particular emphasis will be focus on the physicochemical parameters during the optimisation process (log P, solubility, LE…)

ESR 6 will be also involved in the optimisation process of the hit identified by ESR 3, ESR 8 or ESR 9.
Chemical probes of the inhibitors will be sent to ESR 12 to demonstrate target engagement.

Supervisor: Peter Maas

Secondments: Helmholtz-Zentrum für Infektionsforschung (HZI) / Academia

University of Dundee (UNIVDUN) / Academia

ESR 7: Catalytic mechanism and inhibition of IspG and IspH

The last two enzymes, IspG and IspH, are metalloenzymes containing a highly oxygen-sensitive [4Fe-4S] cluster and follow a particular mechanism in which the substrate binds to the [4Fe-4S] cluster. The known IspG and IspH inhibitors lack antibacterial activity. Following a multidisciplinary approach, which spans from chemistry to enzymology and structural biology (collaboration with ESR 3, WP 1), ESR 7 has the goal to achieve antibacterial activity.

In cellulo activity determination which is led by the WP 3 will ensure in vivo profile.

Supervisor: Prof. Dr. Myriam Seemann

Secondments: Universiteit Gent (UGent) / Academia

Specs / Industry