Chemogenomic Fingerprints Associated with Stage-Specific Gametocytocidal Compound Action against Human Malaria Parasites.
Chemogenomic Fingerprints Associated with Stage-Specific Gametocytocidal Compound Action against Human Malaria Parasites.
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与针对人类疟疾寄生虫的阶段特异性杀配子细胞复合作用相关的化学基因组指纹。
DOI：
10.1021/acsinfecdis.1c00373
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发表时间：
2021
影响因子：
5.3
通讯作者：
Birkholtz,Lyn-Marié
中科院分区：
文献类型：
--
作者：
Niemand,Jandeli;vanBiljon,Riëtte;vanderWatt,Mariëtte;vanHeerden,Ashleigh;Reader,Janette;vanWyk,Roelof;Orchard,Lindsey;Chibale,Kelly;Llinás,Manuel;Birkholtz,Lyn-Marié
激酶抑制剂以前揭示了化合物对恶性疟原虫配子体的不同阶段具有不同的活性。MMV 666810（一种2-氨基吡嗪）对晚期配子体的活性更高，而吡唑并吡啶MMV 674850优先靶向早期配子体。在这里，我们使用深入的转录组指纹分析来探索这种差异阶段特异性杀伤的生物学机制。MMV 674850处理后观察到化合物特异性化学基因组学特征，与无性血液期寄生虫和早期配子母细胞（而非晚期配子母细胞）之间共有的生物学过程相关。MMV 666810具有独特的特征，具有主要与晚期配子体发育相关的成簇基因集，包括Ca 2+依赖性蛋白激酶（CDPK 1和5）和丝氨酸/苏氨酸蛋白激酶（FIKK）。因此，化学基因组分析突出了转录水平上晚期配子体中的重要过程。这一信息对于优先考虑优先损害晚期配子母细胞的化合物以进一步开发为传播阻断抗疟药是重要的。
Kinase-focused inhibitors previously revealed compounds with differential activity against different stages ofPlasmodium falciparumgametocytes. MMV666810, a 2-aminopyrazine, is more active on late-stage gametocytes, while a pyrazolopyridine, MMV674850, preferentially targets early-stage gametocytes. Here, we probe the biological mechanisms underpinning this differential stage-specific killing using in-depth transcriptome fingerprinting. Compound-specific chemogenomic profiles were observed with MMV674850 treatment associated with biological processes shared between asexual blood stage parasites and early-stage gametocytes but not late-stage gametocytes. MMV666810 has a distinct profile with clustered gene sets associated primarily with late-stage gametocyte development, including Ca2+-dependent protein kinases (CDPK1 and 5) and serine/threonine protein kinases (FIKK). Chemogenomic profiling therefore highlights essential processes in late-stage gametocytes, on a transcriptional level. This information is important to prioritize compounds that preferentially compromise late-stage gametocytes for further development as transmission-blocking antimalarials.
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影响因子：
3
作者：
Ghosh AK;Dinglasan RR;Ikadai H;Jacobs-Lorena M
通讯作者：
Jacobs-Lorena M
影响因子：
5.2
作者：
van der Watt, Mariette E.;Reader, Janette;Birkholtz, Lyn-Marie
通讯作者：
Birkholtz, Lyn-Marie
影响因子：
4.9
作者：
Green JL;Moon RW;Whalley D;Bowyer PW;Wallace C;Rochani A;Nageshan RK;Howell SA;Grainger M;Jones HM;Ansell KH;Chapman TM;Taylor DL;Osborne SA;Baker DA;Tatu U;Holder AA
通讯作者：
Holder AA
影响因子：
4.6
作者：
van Biljon R;Niemand J;van Wyk R;Clark K;Verlinden B;Abrie C;von Grüning H;Smidt W;Smit A;Reader J;Painter H;Llinás M;Doerig C;Birkholtz LM
通讯作者：
Birkholtz LM
影响因子：
10.5
作者：
Josling GA;Williamson KC;Llinás M
通讯作者：
Llinás M