Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Gregory M. LaMonte; Frances Rocamora; Danushka S. Marapana; Nina F. Gnädig; Sabine Ottilie; Madeline R. Luth; Tilla S. Worgall; Gregory M. Goldgof; Roxanne Mohunlal; T. R. Santha Kumar; Jennifer K. Thompson; Edgar Vigil; Jennifer Yang; Dylan Hutson; Trevor Johnson; Jianbo Huang; Roy M. Williams; Bing Yu Zou; Andrea L. Cheung; Prianka Kumar; Timothy J. Egan; Marcus C.S. Lee; Dionicio Siegel; Alan F. Cowman; David A. Fidock; Elizabeth A. Winzeler

doi:10.1038/s41467-020-15440-4

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Gregory M. LaMonte
, Frances Rocamora
, Danushka S. Marapana
, Nina F. Gnädig
, Sabine Ottilie
, Madeline R. Luth
, Tilla S. Worgall
, Gregory M. Goldgof
, Roxanne Mohunlal
, T. R. Santha Kumar
, Jennifer K. Thompson
, Edgar Vigil
, Jennifer Yang
, Dylan Hutson
, Trevor Johnson
, Jianbo Huang
, Roy M. Williams
, Bing Yu Zou
, Andrea L. Cheung
, Prianka Kumar

Timothy J. Egan, Marcus C.S. Lee, Dionicio Siegel, Alan F. Cowman, David A. Fidock, Elizabeth A. Winzeler (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

110 Downloads (Pure)

Abstract

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Original language	English
Article number	1780
Number of pages	15
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15440-4
Publication status	Published - 14 Apr 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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Final published versionFinal published version, 2.19 MBLicence: CC BY

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LaMonte, G. M., Rocamora, F., Marapana, D. S., Gnädig, N. F., Ottilie, S., Luth, M. R., Worgall, T. S., Goldgof, G. M., Mohunlal, R., Santha Kumar, T. R., Thompson, J. K., Vigil, E., Yang, J., Hutson, D., Johnson, T., Huang, J., Williams, R. M., Zou, B. Y., Cheung, A. L., ... Winzeler, E. A. (2020). Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway. Nature Communications, 11(1), Article 1780. https://doi.org/10.1038/s41467-020-15440-4

@article{1a8ac013815b47159e39aa3bae74b006,

title = "Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway",

abstract = "A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.",

author = "LaMonte, \{Gregory M.\} and Frances Rocamora and Marapana, \{Danushka S.\} and Gn{\"a}dig, \{Nina F.\} and Sabine Ottilie and Luth, \{Madeline R.\} and Worgall, \{Tilla S.\} and Goldgof, \{Gregory M.\} and Roxanne Mohunlal and \{Santha Kumar\}, \{T. R.\} and Thompson, \{Jennifer K.\} and Edgar Vigil and Jennifer Yang and Dylan Hutson and Trevor Johnson and Jianbo Huang and Williams, \{Roy M.\} and Zou, \{Bing Yu\} and Cheung, \{Andrea L.\} and Prianka Kumar and Egan, \{Timothy J.\} and Lee, \{Marcus C.S.\} and Dionicio Siegel and Cowman, \{Alan F.\} and Fidock, \{David A.\} and Winzeler, \{Elizabeth A.\}",

note = "Funding Information: We would like to thank the members of the Winzeler lab for technical support, reagents and critical reading of the manuscript. G.L. is supported by an AP Giannini post-doctoral fellowship. S.O. and G.M.G. were funded by the Bill and Melinda Gates Foundation (OPP1054480, and OPP1171497). T.J.E. and R.M. were supported by the National Research Foundation of South Africa (Grant No. 91516). R.M. also acknowledges the University of Cape Town for a travel grant. M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). M.C.L gratefully acknowledges funding from Wellcome and the Bill and Melinda Gates Foundation. D.A.F. gratefully acknowledges funding from the Medicines for Malaria Venture and the Bill \& Melinda Gates Foundation. E.A.W. is supported by grants from the NIH (5R01AI090141 and R01AI103058) and by grants from the Bill \& Melinda Gates Foundation (OPP1086217and OPP1141300) as well as by Medicines for Malaria Venture (MMV). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = apr,

day = "14",

doi = "10.1038/s41467-020-15440-4",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

LaMonte, GM, Rocamora, F, Marapana, DS, Gnädig, NF, Ottilie, S, Luth, MR, Worgall, TS, Goldgof, GM, Mohunlal, R, Santha Kumar, TR, Thompson, JK, Vigil, E, Yang, J, Hutson, D, Johnson, T, Huang, J, Williams, RM, Zou, BY, Cheung, AL, Kumar, P, Egan, TJ, Lee, MCS, Siegel, D, Cowman, AF, Fidock, DA & Winzeler, EA 2020, 'Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway', Nature Communications, vol. 11, no. 1, 1780. https://doi.org/10.1038/s41467-020-15440-4

TY - JOUR

T1 - Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

AU - LaMonte, Gregory M.

AU - Rocamora, Frances

AU - Marapana, Danushka S.

AU - Gnädig, Nina F.

AU - Ottilie, Sabine

AU - Luth, Madeline R.

AU - Worgall, Tilla S.

AU - Goldgof, Gregory M.

AU - Mohunlal, Roxanne

AU - Santha Kumar, T. R.

AU - Thompson, Jennifer K.

AU - Vigil, Edgar

AU - Yang, Jennifer

AU - Hutson, Dylan

AU - Johnson, Trevor

AU - Huang, Jianbo

AU - Williams, Roy M.

AU - Zou, Bing Yu

AU - Cheung, Andrea L.

AU - Kumar, Prianka

AU - Egan, Timothy J.

AU - Lee, Marcus C.S.

AU - Siegel, Dionicio

AU - Cowman, Alan F.

AU - Fidock, David A.

AU - Winzeler, Elizabeth A.

N1 - Funding Information: We would like to thank the members of the Winzeler lab for technical support, reagents and critical reading of the manuscript. G.L. is supported by an AP Giannini post-doctoral fellowship. S.O. and G.M.G. were funded by the Bill and Melinda Gates Foundation (OPP1054480, and OPP1171497). T.J.E. and R.M. were supported by the National Research Foundation of South Africa (Grant No. 91516). R.M. also acknowledges the University of Cape Town for a travel grant. M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). M.C.L gratefully acknowledges funding from Wellcome and the Bill and Melinda Gates Foundation. D.A.F. gratefully acknowledges funding from the Medicines for Malaria Venture and the Bill & Melinda Gates Foundation. E.A.W. is supported by grants from the NIH (5R01AI090141 and R01AI103058) and by grants from the Bill & Melinda Gates Foundation (OPP1086217and OPP1141300) as well as by Medicines for Malaria Venture (MMV). Publisher Copyright: © 2020, The Author(s).

PY - 2020/4/14

Y1 - 2020/4/14

N2 - A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

AB - A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

UR - https://www.scopus.com/pages/publications/85083545461

U2 - 10.1038/s41467-020-15440-4

DO - 10.1038/s41467-020-15440-4

M3 - Article

C2 - 32286267

AN - SCOPUS:85083545461

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1780

ER -

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

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