Three new roads leading to a common pathway

Three new roads leading to a common pathway

Over the last few years, research into finding new compounds to kill the malaria parasite has focused on testing compounds directly against the parasite. Once active series have been found, research teams then try to find how they work at a molecular level. An early success here was the identification by a collaboration between Novartis and Swiss Tropical and Public Health Institute, of spiroindolone inhibitors and the elucidation of their molecular target known as PfATP4. Although this protein was identified over 20 years ago, it is a membrane ion pump and difficult to work with, and so has not been the favoured target for those trying to rationally design the next generation of potential medicines.

So far, by testing compounds directly against the parasite, MMV and our partners have discovered almost 30,000 compounds. Recent results of a representative subset show that at least 7% of compounds in the MMV Malaria Box impact the PfATP4 pathway.1 The most advanced, KAE609, has shown activity in patients2, and is now being prepared for combination clinical studies. Thus, despite not being the favoured target over the last decade, PfATP4 has shown itself to be an Achilles heel of the parasite. 

Three other groups have independently identified compounds interacting with PfATP4:

  • SJ733 was developed from the structurally unique dihydroisoquinolone chemical series and was the product of collaboration between St Jude Children’s Research Hospital, USA; Rutgers University, USA; National Institutes of Health, USA; and MMV. The full summary of the preclinical candidate and extensive biological characterization is covered in PNAS3. It is now being prepared for first-in-human studies in 2015 in collaboration with Eisai, funded by Japan’s Global Health Innovation Technology (GHIT).
  • 21A092, pyrazoleamide, was identified from the joint efforts of Drexel University, Philadelphia; University of Washington, Seattle;  Monash University, Australia; the Genomics Institute of the Novartis Research Foundation and MMV. The path to the candidate and mechanism of action has just been published in Nature Communications.4
  • MMV772, a third structurally diverse series that targets PfATP4, is from a collaboration between MMV and GlaxoSmithKline’s Diseases of the Developing World Group in Tres Cantos, Spain.

These three compounds were recommended for full development by MMV’s External Scientific Advisory Committee over the last 18 months.

Compounds that target Plasmodium ATP4 cause rapid parasite clearance in vivo, and KAE609 has confirmed that this rapid killing is also seen in patients. They are known to kill gametocytes, thus pointing to their potential transmission-blocking capability. Most importantly, these molecules originate from distinct chemical classes and, potentially, interact with the pathway at different sites. As a result, when resistant parasites are selected in the laboratory, different PfATP4 mutations are found with each molecule that is tested. In theory this means they could be used together to protect each other depending on the precise cross resistance profile.5 What is really exciting is that these compounds seem to be faster acting than the current mainstay of antimalarial therapy. However, unlike artemisinins which have a very short half-life, these compounds are expected to maintain active plasma concentrations ranging from hours to over a week after dosing. This, coupled with their powerful parasite clearance, means they could be part of a new medicine which reduces the current therapy from 3 days down to just a single day. Such a single-dose cure will be essential in the fight to eradicate malaria.

MMV’s strategy to focus on using the parasite at the heart of new, high-throughput screens has delivered many new targets including PfATP4. The convergence of several completely different families of compounds on the same targets reinforces the value of these targets. The fact that these compounds may be able to work together means it is important to take several in parallel into early translational clinical studies. These will help us to identify which are the best molecules to put in combination, and help us ultimately design the best medicines for the battle to eradicate malaria. 

1. Diverse chemotypes disrupt ion homeostasis in the malaria parasite, Molecular Microbiology, 2014.

2. Spiroindolone KAE609 for Falciparum and Vivax Malaria, The New England Journal of Medicine, 2014.

3. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium, Proceedings of the National Academy of Sciences, 2014.

4. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum, Nature Communications, 2014.

5. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance, PNAS, 2014.