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Project

Development of new antimicrobials: Rational design of polyomavirus and mycobacterial inhibitors

Persistent, untreatable infections pose a substantial financial and medical burden on society. Mycobacterium tuberculosis (Mtb) and BK polyomavirus (BKV) are two endemic species that have persisted for more then a century and over 60 years, respectively. Both infections present ongoing challenges to the public health. Within this thesis, novel lead compounds targeting both infections were discovered. In the first part, the thesis focussed on the bacterial infection Mtb. Mtb is the causative agent for tuberculosis.The success of this dreadful disease stems from its remarkable surviving capabilities within the host defence mechanism. Disruption of this homeostasis makes the bacteria more susceptible to both the host’s immune system and the current portfolio of drugs. With the rise of multidrug resistant and extensive drug resistant strains of Mtb, this current portfolio of drugs is steadily shrinking. Wihtin the thesis, novel lead compounds targeting the biosynthetic pathway of mycothiol was synthesised. In order to achieve this goal, the similarities between cysteine ligase (MshC) and different class I tRNA synthetases were exploited. These proteins are well-known targets for the development for antibacterial agents. These compounds were subsequently used to elucidate the very first full-length crystal structure of MshC with a ligand bound in the active site.

The second part of the thesis focussed on the viral BKV infection. BKV is the causative agent of Polyomavirus-associated nephropathy and haemorrhagic cystitis in kidney and stem cell transplant recipients. The discovery of effective treatments is greatly hampered by the lack of viable antiviral targets. As BKV is a non-enveloped virus, capsid inhibitors offer an interesting method for the discovery of novel BKV inhibitors. The capsid of BKV consists of 72 viral protein 1 (VP1) pentamers, each of which is stabilised through the C-terminal arm of neighbouring pentamers. The capsid is further stabilized by the VP2 and VP3 proteins located on the inside of the central pore. A previously performed crystallographic screening on the VP1 pentamer revealed six novel pockets all located near the edge of different important protein-protein interfaces. The different pockets were further explored through structure-based drug design. This initial research revealed the F50 and R92 pocket to be suitable druggable pockets. This research was expanded by linking two fragments directed to the respective pockets together. The generation of the linkers was aided using DeLinker, an open-source artificial intelligence programme. The different linkers were synthesized and evaluated, leading to a lead compound with low nM affinity for the protein. Subsequently, the effects of the compounds on the viral capsid assembly were evaluated and proved to be effective.

 

Date:1 Oct 2019 →  23 Nov 2023
Keywords:Antimicrobials
Disciplines:Medicinal and biomolecular chemistry not elsewhere classified
Project type:PhD project