Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Janette Reader; Mariëtte E. van der Watt; Dale Taylor; Claire Le Manach; Nimisha Mittal; Sabine Ottilie; Anjo Theron; Phanankosi Moyo; Erica Erlank; Luisa Nardini; Nelius Venter; Sonja Lauterbach; Belinda Bezuidenhout; Andre Horatscheck; Ashleigh van Heerden; Natalie J. Spillman; Anne N. Cowell; Jessica Connacher; Daniel Opperman; Lindsey M. Orchard; Manuel Llinás; Eva S. Istvan; Daniel E. Goldberg; Grant A. Boyle; David Calvo; Dalu Mancama; Theresa L. Coetzer; Elizabeth A. Winzeler; James Duffy; Lizette L. Koekemoer; Gregory Basarab; Kelly Chibale; Lyn Marié Birkholtz

doi:10.1038/s41467-020-20629-8

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Janette Reader, Mariëtte E. van der Watt, Dale Taylor, Claire Le Manach, Nimisha Mittal, Sabine Ottilie, Anjo Theron, Phanankosi Moyo, Erica Erlank, Luisa Nardini, Nelius Venter, Sonja Lauterbach, Belinda Bezuidenhout, Andre Horatscheck, Ashleigh van Heerden, Natalie J. Spillman, Anne N. Cowell, Jessica Connacher, Daniel Opperman, Lindsey M. OrchardManuel Llinás, Eva S. Istvan, Daniel E. Goldberg, Grant A. Boyle, David Calvo, Dalu Mancama, Theresa L. Coetzer, Elizabeth A. Winzeler, James Duffy, Lizette L. Koekemoer, Gregory Basarab, Kelly Chibale, Lyn Marié Birkholtz

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Abstract

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H⁺-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

Original language	English (US)
Article number	269
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20629-8
State	Published - Dec 1 2021

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-020-20629-8

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Reader, J., van der Watt, M. E., Taylor, D., Le Manach, C., Mittal, N., Ottilie, S., Theron, A., Moyo, P., Erlank, E., Nardini, L., Venter, N., Lauterbach, S., Bezuidenhout, B., Horatscheck, A., van Heerden, A., Spillman, N. J., Cowell, A. N., Connacher, J., Opperman, D., ... Birkholtz, L. M. (2021). Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box. Nature communications, 12(1), [269]. https://doi.org/10.1038/s41467-020-20629-8

@article{79cb2bb7c1e84014a58aac1c45c0662a,

title = "Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box",

abstract = "Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.",

author = "Janette Reader and {van der Watt}, {Mari{\"e}tte E.} and Dale Taylor and {Le Manach}, Claire and Nimisha Mittal and Sabine Ottilie and Anjo Theron and Phanankosi Moyo and Erica Erlank and Luisa Nardini and Nelius Venter and Sonja Lauterbach and Belinda Bezuidenhout and Andre Horatscheck and {van Heerden}, Ashleigh and Spillman, {Natalie J.} and Cowell, {Anne N.} and Jessica Connacher and Daniel Opperman and Orchard, {Lindsey M.} and Manuel Llin{\'a}s and Istvan, {Eva S.} and Goldberg, {Daniel E.} and Boyle, {Grant A.} and David Calvo and Dalu Mancama and Coetzer, {Theresa L.} and Winzeler, {Elizabeth A.} and James Duffy and Koekemoer, {Lizette L.} and Gregory Basarab and Kelly Chibale and Birkholtz, {Lyn Mari{\'e}}",

note = "Funding Information: We thank the MMV for assembly and supply of the PRB and Didier Leroy and Esperanza Herreros from the MMV for helpful discussions. We thank Annette Bennett for prior optimization of the SMFA. We thank the Medicines for Malaria Venture and South African Technology Innovation Agency (TIA) for funding (Project MMV18/0001). This project was in part supported by the South African Medical Research Council with funds received from the South African Department of Science and Innovation, in partnership with the Medicines for Malaria Venture (KC, LMB, LLK and TLC); and the DST/NRF South African Research Chairs Initiative Grant (LMB UID: 84627, LLK UID: 171215294399; KC UID: 64767); and CSIR Parliamentary Grant funding (AT, DM). EAW and EI thanks the Bill and Melinda Gates Foundation for funding (OPP1054480 and OPP 1054480) and NS was funded by the Australian NHMRC (APP1072217). Funding Information: Ethics statement. This work holds ethical approval from the University of Pretoria Health Sciences Ethics Committee (506/2018), University of Cape Town: AEC017/026, University of the Witwatersrand Human Research Ethics Committee (M130569) and Animal Ethics Committee (20190701-7O), CSIR Research Ethics Committee (Ref 10/2011) and Scripps Research{\textquoteright}s Normal Blood Donor Service (NBDS), with approval under IRB Number 125933. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-020-20629-8",

language = "English (US)",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Reader, J, van der Watt, ME, Taylor, D, Le Manach, C, Mittal, N, Ottilie, S, Theron, A, Moyo, P, Erlank, E, Nardini, L, Venter, N, Lauterbach, S, Bezuidenhout, B, Horatscheck, A, van Heerden, A, Spillman, NJ, Cowell, AN, Connacher, J, Opperman, D, Orchard, LM, Llinás, M, Istvan, ES, Goldberg, DE, Boyle, GA, Calvo, D, Mancama, D, Coetzer, TL, Winzeler, EA, Duffy, J, Koekemoer, LL, Basarab, G, Chibale, K & Birkholtz, LM 2021, 'Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box', Nature communications, vol. 12, no. 1, 269. https://doi.org/10.1038/s41467-020-20629-8

TY - JOUR

T1 - Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

AU - Reader, Janette

AU - van der Watt, Mariëtte E.

AU - Taylor, Dale

AU - Le Manach, Claire

AU - Mittal, Nimisha

AU - Ottilie, Sabine

AU - Theron, Anjo

AU - Moyo, Phanankosi

AU - Erlank, Erica

AU - Nardini, Luisa

AU - Venter, Nelius

AU - Lauterbach, Sonja

AU - Bezuidenhout, Belinda

AU - Horatscheck, Andre

AU - van Heerden, Ashleigh

AU - Spillman, Natalie J.

AU - Cowell, Anne N.

AU - Connacher, Jessica

AU - Opperman, Daniel

AU - Orchard, Lindsey M.

AU - Llinás, Manuel

AU - Istvan, Eva S.

AU - Goldberg, Daniel E.

AU - Boyle, Grant A.

AU - Calvo, David

AU - Mancama, Dalu

AU - Coetzer, Theresa L.

AU - Winzeler, Elizabeth A.

AU - Duffy, James

AU - Koekemoer, Lizette L.

AU - Basarab, Gregory

AU - Chibale, Kelly

AU - Birkholtz, Lyn Marié

N1 - Funding Information: We thank the MMV for assembly and supply of the PRB and Didier Leroy and Esperanza Herreros from the MMV for helpful discussions. We thank Annette Bennett for prior optimization of the SMFA. We thank the Medicines for Malaria Venture and South African Technology Innovation Agency (TIA) for funding (Project MMV18/0001). This project was in part supported by the South African Medical Research Council with funds received from the South African Department of Science and Innovation, in partnership with the Medicines for Malaria Venture (KC, LMB, LLK and TLC); and the DST/NRF South African Research Chairs Initiative Grant (LMB UID: 84627, LLK UID: 171215294399; KC UID: 64767); and CSIR Parliamentary Grant funding (AT, DM). EAW and EI thanks the Bill and Melinda Gates Foundation for funding (OPP1054480 and OPP 1054480) and NS was funded by the Australian NHMRC (APP1072217). Funding Information: Ethics statement. This work holds ethical approval from the University of Pretoria Health Sciences Ethics Committee (506/2018), University of Cape Town: AEC017/026, University of the Witwatersrand Human Research Ethics Committee (M130569) and Animal Ethics Committee (20190701-7O), CSIR Research Ethics Committee (Ref 10/2011) and Scripps Research’s Normal Blood Donor Service (NBDS), with approval under IRB Number 125933. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

AB - Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

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U2 - 10.1038/s41467-020-20629-8

DO - 10.1038/s41467-020-20629-8

M3 - Article

C2 - 33431834

AN - SCOPUS:85099193777

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 269

ER -

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

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