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靶向脯氨酰-tRNA合成酶的ATP模拟物作为抗疟药物开发的新途径。

ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development.

作者信息

Mishra Siddhartha, Malhotra Nipun, Laleu Benoît, Chakraborti Soumyananda, Yogavel Manickam, Sharma Amit

机构信息

Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.

ICMR-National Institute of Malaria Research (NIMR), Dwarka, New Delhi 110077, India.

出版信息

iScience. 2024 May 22;27(7):110049. doi: 10.1016/j.isci.2024.110049. eCollection 2024 Jul 19.

DOI:10.1016/j.isci.2024.110049
PMID:39104570
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11298890/
Abstract

The prolyl-tRNA synthetase (PRS) is an essential enzyme for protein translation and a validated target against malaria parasite. We describe five ATP mimetics (L95, L96, L97, L35, and L36) against PRS, exhibiting enhanced thermal stabilities in co-operativity with L-proline. L35 displays the highest thermal stability akin to halofuginone, an established inhibitor of PRS. Four compounds exhibit nanomolar inhibitory potency against PRS. L35 exhibits the highest potency of ∼1.6 nM against asexual-blood-stage (ABS) and ∼100-fold (effective concentration [EC]) selectivity for the parasite. The macromolecular structures of PRS with L95 and L97 in complex with L-pro reveal their binding modes and catalytic site malleability. Arg401 of PRS oscillates between two rotameric configurations when in complex with L95, whereas it is locked in one of the configurations due to the larger size of L97. Harnessing such specific and selective chemical features holds significant promise for designing potential inhibitors and expediting drug development efforts.

摘要

脯氨酰 - tRNA合成酶（PRS）是蛋白质翻译所必需的酶，也是抗疟原虫的一个经过验证的靶点。我们描述了五种针对PRS的ATP模拟物（L95、L96、L97、L35和L36），它们与L - 脯氨酸协同作用时表现出增强的热稳定性。L35表现出与已有的PRS抑制剂常山酮类似的最高热稳定性。四种化合物对PRS表现出纳摩尔级的抑制效力。L35对无性血液期（ABS）表现出最高效力，约为1.6 nM，对疟原虫具有约100倍（有效浓度[EC]）的选择性。PRS与L95和L97以及L - 脯氨酸形成复合物的大分子结构揭示了它们的结合模式和催化位点的可塑性。当与L95结合时，PRS的Arg401在两种旋转异构体构型之间振荡，而由于L97的尺寸较大，它被锁定在其中一种构型中。利用这些特定和选择性的化学特征对于设计潜在抑制剂和加快药物研发工作具有重大前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/fd6b97f7e703/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/b292dd9bc27c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/addb32a6694f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/ba257e8478f9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/afedaf96b14f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/6585ebe8e61b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/3db8df039f31/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/195862d887db/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/fd6b97f7e703/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/b292dd9bc27c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/addb32a6694f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/ba257e8478f9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/afedaf96b14f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/6585ebe8e61b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/3db8df039f31/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/195862d887db/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f823/11298890/fd6b97f7e703/gr7.jpg

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