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

被引：8

作者：

Dans, Madeline G. ^{[1
,2
,3
,4
,5
]}

Boulet, Coralie ^{[1
,13
]}

Watson, Gabrielle M. ^{[2
,5
]}

Nguyen, William ^{[2
,5
]}

Dziekan, Jerzy M. ^{[2
,5
]}

Evelyn, Cindy ^{[2
,5
]}

Reaksudsan, Kitsanapong ^{[2
,5
]}

Mehra, Somya ^{[1
,3
,4
]}

Razook, Zahra ^{[1
,3
,4
]}

Geoghegan, Niall D. ^{[2
,5
]}

Mlodzianoski, Michael J. ^{[2
,5
]}

Goodman, Christopher Dean ^{[6
]}

Ling, Dawson B. ^{[1
]}

Jonsdottir, Thorey K. ^{[1
,7
,8
,9
]}

Tong, Joshua ^{[2
]}

Famodimu, Mufuliat Toyin ^{[10
]}

Kristan, Mojca ^{[11
]}

Pollard, Harry ^{[11
]}

Stewart, Lindsay B. ^{[11
]}

Brandner-Garrod, Luke ^{[11
]}

Sutherland, Colin J. ^{[10
,11
]}

Delves, Michael J. ^{[10
]}

Mcfadden, Geoffrey I. ^{[6
]}

Barry, Alyssa E. ^{[1
,3
,4
]}

Crabb, Brendan S. ^{[1
,7
,12
]}

de Koning-Ward, Tania F. ^{[3
,4
]}

Rogers, Kelly L. ^{[2
,5
]}

Cowman, Alan F. ^{[2
,5
]}

Tham, Wai-Hong ^{[2
,5
]}

Sleebs, Brad E. ^{[2
,5
]}

Gilson, Paul R. ^{[1
,7
]}

机构：

[1] Burnet Inst, Melbourne, Vic 3004, Australia

[2] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[3] Deakin Univ, Sch Med, Inst Mental & Phys Hlth & Clin Translat IMPACT, Geelong, Vic 3220, Australia

[4] Deakin Univ, Sch Med, Geelong, Vic 3220, Australia

[5] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[6] Univ Melbourne, Sch Biosci, Parkville, Vic 3010, Australia

[7] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia

[8] Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden

[9] Lab Mol Infect Med Sweden MIMS, Umea, Sweden

[10] London Sch Hyg & Trop Med, Dept Infect Biol, Fac Infect & Trop Dis, London WC1E 7HT, England

[11] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Wellcome Trust Human Malaria Transmiss Facil, London WC1E 7HT, England

[12] Monash Univ, Melbourne, Vic 3800, Australia

[13] Univ Geneva, Dept Microbiol & Mol Med, CH-1206 Geneva, Switzerland

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

IN-VITRO; ARTEMISININ RESISTANCE; MALARIA SPOROZOITES; INVASION; CELLS; INHIBITOR; STAGE; IDENTIFICATION; TRANSCRIPTOME; TRAFFICKING;

D O I：

10.1038/s41467-024-49491-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：19

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