Principal Investigator (PI)
The Foundation is providing £147,854 in support.
Yinuo Wang
Expertise: this project concerns tRNA synthetase inhibitors. We would benefit greatly from the expertise and learnings at GSK related to these targets for malaria, e.g., relevant resistance mechanisms. Our hypothesis, that it is possible to develop compounds like OSM-S-106 as multi[1]targeting agents, would benefit from ongoing peer-review by GSK scientists in response to the data. To clarify the potential of these molecules as drugs, we would benefit from the hit-to-lead team’s medicinal chemistry expertise e.g., for slowing intrinsic clearance.
Resources: GSK hosts significant, relevant resources that will allow much of this work to be completed in the term of the grant (e.g., clearance, solubility), including resources specific to malaria research, such as the PRR assay.
Contacts: Carrying out this project with GSK will help raise the project profile and likely enable us to reach more researchers both with an interest in such compounds for tRNA synthetase inhibition, but also across other targets beyond the scope of the grant. It should be made clear that GSK has already contributed to this project through the discovery of OSM-S-106! There are further scaffolds suitable for reaction hijacking in GSK’s internal library, and we would hope to validate these through data mining/testing.
The Open Source Malaria (OSM) consortium aims to develop open-access antimalarial compounds to combat drug-resistant Plasmodium falciparum. In collaboration with GSK Tres Cantos and the Medicines for Malaria Venture in 2010, we selected OSM-S-106 (TCMDC-135294, MMV025100), a thienopyrimidine-based sulfonamide, as one of the initial series for hit-to-lead optimisation. This molecule continues to show great promise for further development due to its potency, solubility, low toxicity, low molecular weight and low propensity for the development of resistance.
Through collaboration with MMV, MALDA and others, we have recently demonstrated that OSM-S-106 possesses a novel mechanism of action, a “reaction hijacking” inhibition of P. falciparum asparagine tRNA synthetase (Pf AsnRS). (1). OSM-S-106 intercepts the tRNA-Asn conjugate, forming a covalent bond with the amino acid and generating a potent inhibitor in situ. We have acquired preliminary data suggesting the same molecule targets two additional tRNA synthetases.
Our findings raise three fascinating research questions:
1) Can we adopt the same approach to inhibit more Pfal tRNA synthetases?
2) Might such compounds be effective drug candidates?
3) Might these molecules inhibit tRNA synthetases in other pathogens?
To answer questions 1) and 2), we are seeking a collaboration with GSK Tres Cantos to explore the potential of this new compound class (i.e., OSM-S-106 and its potent amino acid derivatives) through hit optimisation, e.g., potency, pharmacokinetic properties, in vitro DMPK and in vitro safety if available. To answer 3), e.g., phenotypic evaluation vs other pathogens, we will seek separate funding.
We will provide protocols for, and initial samples of, OSM-S-106 and its derivatives, and the open science expertise to maximise the advantage to the wider research community. We seek the expertise and resources at Tres Cantos to improve the compounds through chemical synthesis and validation of their potential through in-house assays. We will provide a broader collaborative network to answer other key questions, e.g. molecular biology, validation of on-target activity.
(1). Xie SC, Wang Y, Morton CJ, et al. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. Nat. Commun. 2024, 15:937. doi: 10.1038/s41467-024-45224-z