Principal Investigator (PI)
The Foundation is providing £131,240 in support.
Stefan Jackenroll - Peter Jervis
GSK's contribution to the project will be in kind, and their expertise in hit-to-lead optimisation of small molecules including access to both in vitro and in vivo DMPK and efficacy studies.
Current TB treatment programmes are losing their efficacy, due, at least in part, to the rise of multi-drug- and extensively-drug-resistant TB. It is therefore essential that new drugs, ideally with novel targets, be developed. In light of their involvement in protein biosynthesis, aminoacyl-tRNA synthetases (aaRSs) are very attractive drug targets [1]; indeed, several natural products and non-hydrolysable aminoacyl adenylate analogues have been shown to inhibit this class of enzyme in vitro; however, further development of these inhibitors has often been thwarted by their inability to penetrate the bacterial cell envelope effectively and by cross-reactivity against other protein targets. We, and very recently, Sacchettini [2], have independently shown that compound A possesses whole-cell anti-tuberculosis (TB) activity by targeting M. tuberculosis AspRS. A represents a novel structure for an aaRS inhibitor and is the first such inhibitor of M. tb AspRS. We now seek to undertake a hit-to-lead optimisation of A to accelerate the potential of developing this class of inhibitor against a novel and demonstrably essential M. tuberculosis target.