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New preclinical candidate for the treatment of visceral leishmaniasis

Read the paper

This month the WCAIR Mode of Action group, DDU Kinetoplastid team and collaborators from GSK have published a potential new medicine to treat visceral leishmaniasis (VL).

cru-EM structure showing DDU VL pre-clinical candidate bound to its target
Fig. 5 from PNAS 116 (19) 9318-9323

VL is a parasitic disease that kills 20-40000 people per year. Most of the people afflicted are in Asia, Africa and Latin America. We need safer, more effective oral drugs to treat it as the current treatments have several serious problems. These include the need for cold storage, severe side effects and significant levels of drug resistance. Existing medicines are not well suited for use in the resource poor settings where this disease is endemic.

In this PNAS paper (1), we detail the development of a compound capable of curing VL in a mouse model of the disease. In this setting, the compound proved as effective as a current front-line VL drug. The compound also has good biological and safety properties. It has, therefore, been selected to move onto the next stages of development where we hope it will advance into human clinical trials

Studies by the Mode of Action group revealed that the compound acts by inhibiting the function of the proteasome. This is a multi-subunit complex within the parasite. Normally, it degrades unneeded or damaged proteins by proteolysis. Our new compound inhibits the chymotrypsin-like activity of the proteasome. Inhibiting this activity leads to cell cycle arrest, killing the parasite

The research was funded by Wellcome.

The paper has been followed by a positive PNAS commentary from Elizabeth Winzeler and Sabine Ottiliea . They end their commentary by saying “Wyllie et al.’s study shows that when all the pieces for drug discovery—including a chemically validated target, a structure, as well as biochemical and cellular assays—are in place, better treatments for neglected diseases can readily be found.” (2) Thank you, we agree!

 

References

  1. Susan Wyllie et al Proceedings of the National Academy of Sciences May 2019, 116 (19) 9318-9323; DOI:10.1073/pnas.1820175116
  2. Elizabeth A. Winzeler, Sabine Ottilie Proceedings of the National Academy of Sciences May 2019, 116 (21) 10198-10200; DOI:10.1073/pnas.1904694116