Harvard School of Public Health and Broad Institute

Start : April 2014 | Status : Complete

The scientists: This project is run by Dr. Leila Ross, an experienced parasitologist from the Department of Immunology and Infectious Diseases led by Dyann Wirth at the University of Harvard. Leila will focus her research on identifying and developing partner drugs for pyrimidine biosynthesis inhibitors that suppress the development of resistance in Plasmodium falciparum.

The sponsor: The Wirth laboratory blends the scientific environments of the Harvard School of Public Health, the Broad Institute, and collaborators from around the globe to create a unique malaria research and training network that brings together scientists with expertise in molecular biology, genetics, genomics, population genetics, chemistry, cell biology, epidemiology, computational biology, and biostatistics with leading clinicians in infectious diseases and pathology. The group has applied state of the art technologies and novel approaches to better understand the fundamental biology of the malaria parasite and mechanisms of drug resistance. The group has been one of the international leaders in technology development for Plasmodium falciparum genotyping and has helped identify over 112,000 genetic singlenucleotide polymorphisms (SNPs) across the P. falciparum genome.

Foundation funding: The Foundation is providing £9,948 in support.

GSK’s contribution: GSK is providing 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.

Project Description: 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.