New strategies are needed to block malaria transmission and eradicate the spread of the disease. None of the commonly used antimalarials are effective against Plasmodium gametocytes, the parasite stage responsible for transmission, and consequently patients can remain infectious for weeks after symptoms have resolved. Our recent screen of > 6000 bioactive molecules, including 400 malaria box compounds identified 7 with < 50nM IC50 against stage III-V gametocytes. One of these, Torin 2 had an IC50 of 8 nM against P. falciparum strain 3D7, which is >1000 times lower than its activity against the mammalian HepG2 cell line. Torin 2 was also equally effective against 2 additional P. falciparum strains, HB3 and Dd2, with distinct geographic origins and drug resistance profiles. Importantly, two 4mg/kg doses completely blocked oocyst formation using the mouse P. berghei model to test in vivo transmission blocking activity. Early structure activity relationship (SAR) analysis done in collaboration with investigators at the National Center for Advancing Translational Research (NCATS) allowed the production of a Torin 2 resin that lead to the identification of Torin 2 interacting proteins. The goals of this proposal are to extend our analysis of Torin 2 by:
Aim 1 : Define the stage specificity and timing of Torin 2 inhibition from intraerythrocytic development to sporozoite formation to inform both drug delivery strategies and mechanistic studies.
Aim 2 : Evaluate the in vivo activity of novel Torin 2 analogs using the rodent malaria model:
Aim 3 : Evaluate the Plasmodium target and mechanism of Torin 2 gametocytocidal activity using both directed and discovery approaches. In addition, to advancing our currently limited understanding of the cellular pathways required for gametocyte viability, the results will provide important new leads for the development of a potent malaria transmission-blocking drug.

Public Health Relevance

The identification of drugs that effectively eliminate the transmission stages of the malaria parasites is critical to the global malaria eradication effects. These stages are not cleared with commonly used antimalarial treatments and can also be generated during asymptomatic infections. Seven compounds with <50nM IC50 against stage III-V gametocytes were identified in our recent gametocytocidal screen and provide an important first step toward the development of a malaria transmission-blocking drug.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114761-06
Application #
9686662
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
O'Neil, Michael T
Project Start
2015-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Krishnan, Karthik Mosur; Williamson, Kim C (2018) The proteasome as a target to combat malaria: hits and misses. Transl Res 198:40-47
Edwards, Rachel L; Brothers, Robert C; Wang, Xu et al. (2017) MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Sci Rep 7:8400
Li, Hao; Sun, Wei; Huang, Xiuli et al. (2017) Efficient Synthesis of 1,9-Substituted Benzo[h][1,6]naphthyridin-2(1H)-ones and Evaluation of their Plasmodium falciparum Gametocytocidal Activities. ACS Comb Sci 19:748-754
Sun, Wei; Huang, Xiuli; Li, Hao et al. (2017) Novel lead structures with both Plasmodium falciparum gametocytocidal and asexual blood stage activity identified from high throughput compound screening. Malar J 16:147
Patel, Paresma R; Sun, Wei; Kim, Myunghoon et al. (2016) In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents. Bioorg Med Chem Lett 26:2907-2911
Panackal, Anil A; Williamson, Kim C; van de Beek, Diederik et al. (2016) Fighting the Monster: Applying the Host Damage Framework to Human Central Nervous System Infections. MBio 7:e01906-15
Maron, Maxim I; Magle, Crystal T; Czesny, Beata et al. (2015) Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050. Antimicrob Agents Chemother 60:1492-9