A consortium of chemists, structural biologists and parasitologists has discovered a series of N-myristoyl transferase inhibitors and identified the features necessary for their novel mode of binding to the enzyme. The work is published in the Journal of Medicinal Chemistry (: 10.1021/jm300040p).

Plasmodium vivax is the second most important cause of malaria in humans and is widely distributed worldwide. It can cause severe morbidity and has a dormant form called the hypnozoite that hibernates in a liver cell until activated. There is an urgent need for new drugs active against vivax malaria parasites, including the hypnozoite form, but it is a very difficult parasite to study because it cannot be cultured easily in the laboratory.

A consortium of scientists based at Imperial College, the Universities of York and Nottingham, and NIMR have focused on the development of inhibitors of the N-myristoyl transferase (NMT) enzyme in parasitic protozoa. They have worked together with MRC Technology to carry out a high throughput screen and identify a series of P. vivax NMT inhibitors. A high resolution crystal structure of a hit compound in complex with NMT has been obtained, allowing its mode of binding to be understood and the design and testing of a set of analogues to explore the features of the inhibitor necessary for activity and selectivity. This information will facilitate the next step of testing compounds against transgenic parasites expressing the P. vivax NMT gene.

N-myristoylation of a protein attaches a C14-fatty acid to its N-terminus, and targets the protein to a membrane. It is expected that ~100 malaria parasite proteins are myristoylated and they play essential roles in key areas of parasite biology such as host cell invasion.

The consortium has a range of complementary skills essential for success in this area and consists of chemists (Robin Leatherbarrow and Ed Tate, Imperial College), structural biologists (Tony Wilkinson and Jim Brannigan, York), and parasite biologists (Tony Holder, NIMR; Debbie Smith, York; and Rita Tewari, Nottingham).

Link: www.nimr.mrc.ac.uk/news/a-drug-target-in-the-second-most-important-cause-of-malaria/