Author: De Souza, Mariana Laureano ; Lafuente-Monasterio, Maria Jose ; Winzeler, Elizabeth ; Blauwkamp, James ; Gamo, Francisco-Javier ; Morano, Alexander ; Farre, Jean-Claude ; Carolino, Krypton ; Ghidelli-Disse, Sonja ; Absalon, Sabrina ; Dvorin, Jeffrey ; Chen, Daisy

The precise mode of action of ganaplacide (KAF156), a phase III antimalarial candidate, remains elusive. Here we employ omics-based methods with the closely related chemical analog, GNF179, to search for potential Plasmodium targets. Ranking potential targets derived from chemical genetics and proteomic affinity chromatography methodologies identifies SEY1, or Synthetic Enhancement of YOP1, which is predicted to encode an essential dynamin-like GTPase implicated in homotypic fusion of endoplasmic reticulum (ER) membranes. We demonstrate that GNF179 decreases Plasmodium SEY1 melting temperature. We further show that GNF179 binds to recombinant Plasmodium SEY1 and subsequently inhibits its GTPase activity, which is required for maintaining ER architecture. Using ultrastructure expansion microscopy, we find GNF179 treatment changes parasite ER and Golgi morphology. We also confirm that SEY1 is an essential gene in P. falciparum. These data suggest that SEY1 may contribute to the mechanism of action of imidazolopiperazines and is a new and attractive druggable target.

12 Dec 2023·Microbiology Spectrum

A conserved metabolic signature associated with response to fast-acting anti-malarial agents

Article

Author: Regnault, Clement ; Yokokawa, Fumiaki ; Straimer, Judith ; Barrett, Michael P ; Taft, Benjamin ; Simwela, Nelson V ; Diagana, Thierry T ; Stokes, Barbara H ; Tavernelli, Luis E ; Guiguemde, W Armand ; Waters, Andrew P

ABSTRACT Characterizing the mode of action of anti-malarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of anti-malarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone. A slow-acting anti-malarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5-h window of drug exposure. In contrast, fast-killing drugs, DHA and the spiroindolone (NITD246), elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of hemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described class of anti-malarial agents of the 5-aryl-2-amino-imidazothiadiazole class also exhibited a fast-acting profile that featured peptide losses indicative of disrupted hemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast-acting anti-malarial compounds generate similar biochemical signatures in Plasmodium pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates. IMPORTANCEIn malaria drug discovery, understanding the mode of action of lead compounds is important as it helps in predicting the potential emergence of drug resistance in the field when these drugs are eventually deployed. In this study, we have employed metabolomics technologies to characterize the potential targets of anti-malarial drug candidates in the developmental pipeline at NITD. We show that NITD fast-acting leads belonging to spiroindolone and imidazothiadiazole class induce a common biochemical theme in drug-exposed malaria parasites which is similar to another fast-acting, clinically available drug, DHA. These biochemical features which are absent in a slower acting NITD lead (GNF17) point to hemoglobin digestion and inhibition of the pyrimidine pathway as potential action points for these drugs. These biochemical themes can be used to identify and inform on the mode of action of fast drug candidates of similar profiles in future drug discovery programs.

15 Jul 2021·Journal of Antimicrobial ChemotherapyQ2 · MEDICINE

Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali

Q2 · MEDICINE

Article

Author: Diallo, Nouhoum ; Sangare, Cheick Papa Oumar ; Haidara, Aboubecrin Sedhigh ; Sogore, Fanta ; Djimde, Abdoulaye A ; Traore, Aliou ; Awandare, Gordon A ; Campo, Brice ; Diakite, Mahamadou ; Aniweh, Yaw ; Diakité, Seidina A S ; Dembele, Laurent

AbstractObjectivesTo evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs.MethodsWe conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691.ResultsWe report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum.ConclusionsOur data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Discovery	US	The Scripps Research Institute	-

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