Hit-to-lead discovery for new anti-malarials in collaboration between MMV and Eisai

To achieve project objectives, multiple hit series were brought to this project from two approaches, GHIT Screening Platform and GPI-biosynthesis inhibitor. Regarding MOA, most of the hit series that will be investigated by Eisai and MMV have shown to have a chemotype different from current available or known antimalarials, and one of the hit series is shown to have a new MOA that inhibits GPI biosynthesis. Furthermore, hit compounds will first be screened to see if their MOA is the same as existing antimalarial drugs, allowing us to prioritize novel MOAs. Multi-stage activities mean to act on parasites in different life stages. In the previous Screening Platform, hit series which showed antimalarial activities in two or more life stages of parasites were selected and brought to this project. Inhibition of GPI-biosynthesis is also expected to lead to antimalarial activities against multiple parasite life stages, because many kinds of stage-specific GPI-anchored proteins are expressed in each life stage of the malaria parasite. The additional advantage of targeting GPI biosynthesis is a novel MOA with an identified target protein. The target protein named as Gwt1p, an acyltransferase essential in GPI-biosynthesis, was discovered in Eisai. This MOA was also evaluated for other pathogenic microorganisms and a candidate compound for clinical trials was identified in the previous antifungal project of Eisai.

Drug-based Strategies

Jan 2014

$750,000

Japan