Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1

Madeline G. Dans; Coralie Boulet; Gabrielle M. Watson; William Nguyen; Jerzy M. Dziekan; Cindy Evelyn; Kitsanapong Reaksudsan; Somya Mehra; Zahra Razook; Niall D. Geoghegan; Michael J. Mlodzianoski; Christopher Dean Goodman; Dawson B. Ling; Thorey K. Jonsdottir; Joshua Tong; Mufuliat Toyin Famodimu; Mojca Kristan; Harry Pollard; Lindsay B. Stewart; Luke Brandner-Garrod; Colin J. Sutherland; Michael J. Delves; Geoffrey I. McFadden; Alyssa E. Barry; Brendan S. Crabb; Tania F. de Koning-Ward; Kelly L. Rogers; Alan F. Cowman; Wai Hong Tham; Brad E. Sleebs; Paul R. Gilson

doi:10.1038/s41467-024-49491-8

Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1

Madeline G. Dans^*, Coralie Boulet, Gabrielle M. Watson, William Nguyen, Jerzy M. Dziekan, Cindy Evelyn, Kitsanapong Reaksudsan, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Michael J. Mlodzianoski, Christopher Dean Goodman, Dawson B. Ling, Thorey K. Jonsdottir, Joshua Tong, Mufuliat Toyin Famodimu, Mojca Kristan, Harry Pollard, Lindsay B. Stewart, Luke Brandner-GarrodColin J. Sutherland, Michael J. Delves, Geoffrey I. McFadden, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Kelly L. Rogers, Alan F. Cowman, Wai Hong Tham, Brad E. Sleebs, Paul R. Gilson^*

^*Corresponding author for this work

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

7 Citations (Scopus)

Abstract

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.

Original language	English
Article number	5219
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49491-8
Publication status	Published - Dec 2024
Externally published	Yes

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Dans, M. G., Boulet, C., Watson, G. M., Nguyen, W., Dziekan, J. M., Evelyn, C., Reaksudsan, K., Mehra, S., Razook, Z., Geoghegan, N. D., Mlodzianoski, M. J., Goodman, C. D., Ling, D. B., Jonsdottir, T. K., Tong, J., Famodimu, M. T., Kristan, M., Pollard, H., Stewart, L. B., ... Gilson, P. R. (2024). Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1. Nature Communications, 15(1), Article 5219. https://doi.org/10.1038/s41467-024-49491-8

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title = "Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1",

abstract = "With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite{\textquoteright}s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.",

author = "Dans, {Madeline G.} and Coralie Boulet and Watson, {Gabrielle M.} and William Nguyen and Dziekan, {Jerzy M.} and Cindy Evelyn and Kitsanapong Reaksudsan and Somya Mehra and Zahra Razook and Geoghegan, {Niall D.} and Mlodzianoski, {Michael J.} and Goodman, {Christopher Dean} and Ling, {Dawson B.} and Jonsdottir, {Thorey K.} and Joshua Tong and Famodimu, {Mufuliat Toyin} and Mojca Kristan and Harry Pollard and Stewart, {Lindsay B.} and Luke Brandner-Garrod and Sutherland, {Colin J.} and Delves, {Michael J.} and McFadden, {Geoffrey I.} and Barry, {Alyssa E.} and Crabb, {Brendan S.} and {de Koning-Ward}, {Tania F.} and Rogers, {Kelly L.} and Cowman, {Alan F.} and Tham, {Wai Hong} and Sleebs, {Brad E.} and Gilson, {Paul R.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-49491-8",

language = "English",

volume = "15",

journal = "Nature Communications",

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Dans, MG, Boulet, C, Watson, GM, Nguyen, W, Dziekan, JM, Evelyn, C, Reaksudsan, K, Mehra, S, Razook, Z, Geoghegan, ND, Mlodzianoski, MJ, Goodman, CD, Ling, DB, Jonsdottir, TK, Tong, J, Famodimu, MT, Kristan, M, Pollard, H, Stewart, LB, Brandner-Garrod, L, Sutherland, CJ, Delves, MJ, McFadden, GI, Barry, AE, Crabb, BS, de Koning-Ward, TF, Rogers, KL, Cowman, AF, Tham, WH, Sleebs, BE & Gilson, PR 2024, 'Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1', Nature Communications, vol. 15, no. 1, 5219. https://doi.org/10.1038/s41467-024-49491-8

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T1 - Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1

AU - Dans, Madeline G.

AU - Boulet, Coralie

AU - Watson, Gabrielle M.

AU - Nguyen, William

AU - Dziekan, Jerzy M.

AU - Evelyn, Cindy

AU - Reaksudsan, Kitsanapong

AU - Mehra, Somya

AU - Razook, Zahra

AU - Geoghegan, Niall D.

AU - Mlodzianoski, Michael J.

AU - Goodman, Christopher Dean

AU - Ling, Dawson B.

AU - Jonsdottir, Thorey K.

AU - Tong, Joshua

AU - Famodimu, Mufuliat Toyin

AU - Kristan, Mojca

AU - Pollard, Harry

AU - Stewart, Lindsay B.

AU - Brandner-Garrod, Luke

AU - Sutherland, Colin J.

AU - Delves, Michael J.

AU - McFadden, Geoffrey I.

AU - Barry, Alyssa E.

AU - Crabb, Brendan S.

AU - de Koning-Ward, Tania F.

AU - Rogers, Kelly L.

AU - Cowman, Alan F.

AU - Tham, Wai Hong

AU - Sleebs, Brad E.

AU - Gilson, Paul R.

PY - 2024/12

Y1 - 2024/12

N2 - With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.

AB - With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.

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DO - 10.1038/s41467-024-49491-8

M3 - Article

C2 - 38890312

AN - SCOPUS:85196204192

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

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ER -

Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1

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