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化学生物组学验证了 M1 丙氨酰氨基肽酶的选择性靶向作为一种抗疟策略。

Chemoproteomics validates selective targeting of M1 alanyl aminopeptidase as an antimalarial strategy.

机构信息

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.

School of Medicine, Deakin University, Geelong, Australia.

出版信息

Elife. 2024 Jul 8;13:RP92990. doi: 10.7554/eLife.92990.

DOI:10.7554/eLife.92990
PMID:38976500
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11230628/
Abstract

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant (A-M1) and (A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets A-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on A-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of A-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

摘要

急需具有新型作用机制的新型抗疟药物来对抗疟原虫耐药性。在这里，我们使用选择性抑制剂 MIPS2673 描述了 M1 丙氨酰金属氨基肽酶作为有吸引力的药物靶点的多组学化学验证。MIPS2673 对重组（A-M1）和（A-M1）M1 金属氨基肽酶表现出很强的抑制作用，对其他人和人类氨基肽酶具有选择性，并且具有出色的体外抗疟活性，对宿主无明显细胞毒性。基于整个寄生虫裂解物热稳定性和有限蛋白酶解的正交无标记化学蛋白质组学方法表明，MIPS2673 仅在寄生虫中靶向 A-M1，有限蛋白酶解还能够将 A-M1 的结合位点估计在 X 射线晶体学确定的结合位点的~5 Å 内。最后，通过非靶向代谢组学进行的功能研究表明，MIPS2673 抑制了 A-M1 在血红蛋白消化中的关键作用。总之，我们的无偏多组学目标分解方法证实了 MIPS2673 的靶标活性，并验证了选择性抑制 M1 丙氨酰金属氨基肽酶作为一种有前途的抗疟策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/9ea3e9ea848c/elife-92990-fig6-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/0bac13da1e4c/elife-92990-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/ec65bdef0ab6/elife-92990-fig4-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/7fc6f4d27b55/elife-92990-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/9ea3e9ea848c/elife-92990-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/0f2a0e83563e/elife-92990-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/5dcb11464e51/elife-92990-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/07d23a805e21/elife-92990-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/d2a252f96327/elife-92990-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/6fc9c740c660/elife-92990-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/0bac13da1e4c/elife-92990-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/ec65bdef0ab6/elife-92990-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/e69c4c0db852/elife-92990-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/bd279fd13d70/elife-92990-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1deb/11230628/8e9828cecdec/elife-92990-fig5-figsupp2.jpg
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