Principal Investigator (PI)
The Foundation is providing £9,948 in support.
Dr. Leila Ross
GSK provides in-kind contributions including facilities and expertise from supporting scientists in Biochemistry, Screening and Medicinal Chemistry for DHODH inhibitors, and also through access to GSK´s collection of compounds.
Drug resistance is reported for nearly every anti-malarial in use. The resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another, combination therapies can be designed that not only kill the parasite, but also guide its evolution away from resistance.
This concept, termed “targeting resistance,” was applied to the malaria enzyme dihydroorotate dehydrogenase (PfDHODH). PfDHODH catalyzes the rate-limiting step in pyrimidine biosynthesis and has been well-validated as an anti-malarial target. In vitro resistance selections with PfDHODH inhibitors led to point mutations in PfDHODH. Characterization of these resistant parasites showed that resistance to one PfDHODH inhibitor did not give cross-resistance to all others; in fact, these strains were now hypersensitive to several other structural classes of inhibitors. Pairing different PfDHODH inhibitor classes largely suppressed the emergence of resistant parasites over 35 generations, which is enough time to mutate every nucleotide in the genome in the population size used.
To further develop this project, the focus will be on the identification of inhibitors of mutant PfDHODH with no residual activity against the wild-type. Novel inhibitors will be employed in studies of the enzymology of DHODH and used in further resistance selection experiments and fitness cost studies.