Thierry Diagana, PhD
Novartis Institute for Tropical Diseases
Drug discovery efforts for new Plasmodium vivax malaria curative therapy have been hindered by our relatively poor understanding of the parasite liver stage biology as well as the dearth of cellular and molecular tools. To evaluate drug efficacy on liver stages, there are animal model(s) of hypnozoite biology—P. cynomolgi in macaques and potentially P. vivax in Aotus monkeys—which are expensive and have very low throughput. Access to a surrogate in vitro cellular system would be thus very valuable for the rapid discovery of new drugs with potency on the Plasmodium liver stage. Recent progress has been made with the P. cynomolgi parasite that, when cultured in simian hepatocytes, develops persistent forms displaying all the pharmacological and biological properties of the hypnozoite. Through several collaborations, we have leveraged this assay to identify a novel series of antimalarial drugs that, through the inhibition of the plasmodium lipid kinase PI4K, kill all the main life-cycle stages of the parasite, including the hypnozoite. Unfortunately this in vitro assay remains of very low throughput and does not allow for large scale screening. In this context, the Novartis Institute for Tropical Diseases aims to develop and validate a technology platform for the high-throughput in vitro evaluation of drugs on Plasmodium’s liver stages, including the hypnozoite.
Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures.
Dembélé L, Franetich JF, Lorthiois A, Gego A, Zeeman AM, Kocken CH, Le Grand R, Dereuddre-Bosquet N, van Gemert GJ, Sauerwein R, Vaillant JC, Hannoun L, Fuchter MJ, Diagana TT, Malmquist NA, Scherf A, Snounou G, Mazier D.
Nat Med. 2014 Mar;20(3):307-12
KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.
Zeeman AM, van Amsterdam SM, McNamara CW, Voorberg-van der Wel A, Klooster EJ, van den Berg A, Remarque EJ, Plouffe DM, van Gemert GJ, Luty A, Sauerwein R, Gagaring K, Borboa R, Chen Z, Kuhen K, Glynne RJ, Chatterjee AK, Nagle A, Roland J, Winzeler EA, Leroy D, Campo B, Diagana TT, Yeung BK, Thomas AW, Kocken CH.
Antimicrob Agents Chemother. 2014 Mar;58(3):1586-95
Targeting Plasmodium PI(4)K to eliminate malaria.
McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Nagle A, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ, Zeeman AM, Dechering KJ, Kumar TR, Henrich PP, Gagaring K, Ibanez M, Kato N, Kuhen KL, Fischli C, Rottmann M, Plouffe DM, Bursulaya B, Meister S, Rameh L, Trappe J, Haasen D, Timmerman M, Sauerwein RW, Suwanarusk R, Russell B, Renia L, Nosten F, Tully DC, Kocken CH, Glynne RJ, Bodenreider C, Fidock DA, Diagana TT, Winzeler EA.
Nature. 2013 Dec 12;504(7479):248-53.
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