Imidazolopiperazines (IZPs) are a novel class of antimalarial drug in clinical development for the treatment of uncomplicated malaria and malaria prophylaxis. IZPs eliminate blood stage infections and both prevent asymptomatic malaria development and malaria transmission in animal models of malaria. One member of the class has been tested in early clinical trials and is well-tolerated by humans when administered orally. Although parasite resistance to IZPs is conferred by mutations in the Plasmodium falciparum gene encoding the parasite P. falciparum cyclic amine resistance locus (PfCARL), the mechanism of action of the IZP's is not well understood. Further studies on how the IZPs work are therefore needed, We propose to use a suite of genomic methods including metabolomics, transcriptomics and other genome-wide methods to study how IZPs act against all Plasmodium lifecycle forms that parasitize humans, with the goal of identifying their precise target. Specifically, we will first use metabolomics profiling to examine how parasite metabolic pathways respond to parasite IZP treatment in blood stages. We will then compare these metabolic responses to the IZPs to the transcriptional response to IZP treatment in blood stages, liver stages and gametocytes. We will also perform similar analyses against compounds with known mechanisms of action, in order to identify IZP specific effects. Second, we will probe for any additional targets using a well-established experimental pipeline of in vitro evolution followed by whole genome sequencing. Genes with identified resistance mutations will be associated with the pathways identified by metabolomic and transcriptional profiling to identify putative targets. Finally, we will confirm any putative targets in P. falciparum through a series o functional studies.

Public Health Relevance

Given the continuing emergence of drug resistance in malaria parasites, there is a clear need for new antimalarial drugs. The imidazolopiperazines are very promising antimalarial drugs currently being tested in human trials. We propose to investigate their activity against malaria parasites in order create better antimalarial drugs, to understand how parasites might become resistant and to improve the efficacy of these drugs in humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-N (02)M)
Program Officer
O'Neil, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Antonova-Koch, Yevgeniya; Meister, Stephan; Abraham, Matthew et al. (2018) Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science 362:
Cowell, Annie N; Istvan, Eva S; Lukens, Amanda K et al. (2018) Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science 359:191-199
Diedrich, Daniela; Stenzel, Katharina; Hesping, Eva et al. (2018) One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. Eur J Med Chem 158:801-813
Luth, Madeline R; Gupta, Purva; Ottilie, Sabine et al. (2018) Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery. ACS Infect Dis 4:301-314
Xie, Stanley C; Gillett, David L; Spillman, Natalie J et al. (2018) Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome. J Med Chem 61:10053-10066
Ma, Shang; Cahalan, Stuart; LaMonte, Gregory et al. (2018) Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection. Cell 173:443-455.e12
LaMonte, Gregory M; Almaliti, Jehad; Bibo-Verdugo, Betsaida et al. (2017) Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity. J Med Chem 60:6721-6732
Rabinovich, Regina N; Drakeley, Chris; Djimde, Abdoulaye A et al. (2017) malERA: An updated research agenda for malaria elimination and eradication. PLoS Med 14:e1002456
Istvan, Eva S; Mallari, Jeremy P; Corey, Victoria C et al. (2017) Esterase mutation is a mechanism of resistance to antimalarial compounds. Nat Commun 8:14240
Cowell, Annie N; Loy, Dorothy E; Sundararaman, Sesh A et al. (2017) Selective Whole-Genome Amplification Is a Robust Method That Enables Scalable Whole-Genome Sequencing of Plasmodium vivax from Unprocessed Clinical Samples. MBio 8:

Showing the most recent 10 out of 42 publications