Molecular basis for the potency and selectivity of DNDI-6690, a promising lead for the development of novel anti-leishmanial drugs.

Chemotherapy is a cornerstone in the battle against leishmaniasis, a neglected tropical disease caused by Leishmania parasites that affects millions worldwide. In addition, currently unaffected areas are confronted with the (re-)emergence of the disease. Unfortunately, an alarming number of reports are describing treatment failure with currently available drugs, which can be traced back to three main mechanisms employed by the parasite to cope with the exposure to chemotherapy: drug resistance, hiding in so-called "sanctuary sites" and parasite quiescence. Given that the current number of anti-leishmanial treatment options is limited and that those available are unsatisfactory, there is a dire need for the discovery of novel compounds, preferably with yet unexplored modes of action. In this quest, DNDI-6690 has been identified as a promising lead. While the molecular target of this compound has been identified, many aspects for the molecular basis of the anti-leishmanial activity of DNDI-6690 remain enigmatic. First, a biophysical and structural characterisation of the target – DNDI-6690 complex is still lacking. Second, the breadth of the compound's activity within the Leishmania genus has not been fully explored. Finally, the link between the action of DNDI-6690 and parasite quiescence remains to be investigated. Given the promising nature of DNDI-6690 and the dire need for novel tools to combat leishmaniasis, this warrants further investigation.

Keywords:DRUG DISCOVERY, MECHANISMS, LEISHMANIA

Disciplines:Molecular biophysics, Structural biology, Compound screening, Drug discovery and development not elsewhere classified

Project type:Collaboration project