鉴定和优化克氏锥虫半胱氨酸蛋白酶抑制剂：克氏锥虫 cruzain、rhodesain 和 TbCatB。
Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
机构信息
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20892-3370, USA.
出版信息
J Med Chem. 2010 Jan 14;53(1):52-60. doi: 10.1021/jm901069a.
Abstract
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.
摘要
克氏锥虫和布氏锥虫分别是引起恰加斯病和非洲昏睡病的寄生虫。这两种寄生虫的生存都依赖于必需的半胱氨酸蛋白酶：克氏锥虫的克氏锥虫半胱氨酸蛋白酶和布氏锥虫的 TbCatB/罗得西亚锥虫半胱氨酸蛋白酶。最近对克氏锥虫半胱氨酸蛋白酶的高通量定量筛选发现，三嗪腈是其他半胱氨酸蛋白酶的已知抑制剂，也是该酶的可逆抑制剂。本文详细介绍的结构修饰，包括将三嗪核心骨架修饰为嘌呤，使该酶对克氏锥虫和罗得西亚锥虫半胱氨酸蛋白酶的体外活性提高了 350 倍，同时对布氏锥虫寄生虫也具有活性。选择的化合物被筛选了一组人类半胱氨酸和丝氨酸蛋白酶，以确定其选择性，并获得了我们最有效的类似物与克氏锥虫半胱氨酸蛋白酶结合的共晶。
相似文献
1
Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
J Med Chem. 2010 Jan 14;53(1):52-60. doi: 10.1021/jm901069a.
2
Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents.
Chemistry. 2012 May 21;18(21):6528-41. doi: 10.1002/chem.201103322. Epub 2012 Apr 4.
3
Structure-Based Optimization of Quinazolines as Cruzain and CATL Inhibitors.
J Med Chem. 2021 Sep 9;64(17):13054-13071. doi: 10.1021/acs.jmedchem.1c01151. Epub 2021 Aug 30.
4
Aryl ureas represent a new class of anti-trypanosomal agents.
Chem Biol. 2000 Sep;7(9):733-42. doi: 10.1016/s1074-5521(00)00018-1.
5
Optimization of triazine nitriles as rhodesain inhibitors: structure-activity relationships, bioisosteric imidazopyridine nitriles, and X-ray crystal structure analysis with human cathepsin L.
ChemMedChem. 2013 Jun;8(6):967-75. doi: 10.1002/cmdc.201300112. Epub 2013 May 9.
6
Nanomolar activity of coumarin-3-thiosemicarbazones targeting Trypanosoma cruzi cruzain and the T. brucei cathepsin L-like protease.
Eur J Med Chem. 2025 Feb 5;283:117109. doi: 10.1016/j.ejmech.2024.117109. Epub 2024 Nov 28.
7
Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1.
Antimicrob Agents Chemother. 2015 May;59(5):2666-77. doi: 10.1128/AAC.04601-14. Epub 2015 Feb 23.
8
Discovery and characterization of trypanocidal cysteine protease inhibitors from the 'malaria box'.
Eur J Med Chem. 2019 Oct 1;179:765-778. doi: 10.1016/j.ejmech.2019.06.062. Epub 2019 Jun 22.
9
Benzimidazole inhibitors of the major cysteine protease of .
Future Med Chem. 2019 Jul;11(13):1537-1551. doi: 10.4155/fmc-2018-0523.
10
Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB.
Bioorg Med Chem Lett. 2008 May 1;18(9):2883-5. doi: 10.1016/j.bmcl.2008.03.083. Epub 2008 Apr 8.
引用本文的文献
1
Investigation of the activity of 4-aminoquinolines as cysteine protease inhibitors with application in the treatment of Chagas disease.
Mem Inst Oswaldo Cruz. 2025 Feb 7;120:e240161. doi: 10.1590/0074-02760240161. eCollection 2025.
2
-Cyanoacrylamides and 5-Imino Pyrrolones against : Activity and Induced Mechanisms of Cell Death.
Trop Med Infect Dis. 2024 Aug 24;9(9):191. doi: 10.3390/tropicalmed9090191.
3
Integrated Computational Approaches for Drug Design Targeting Cruzipain.
Int J Mol Sci. 2024 Mar 27;25(7):3747. doi: 10.3390/ijms25073747.
4
Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations.
Curr Comput Aided Drug Des. 2025;21(1):67-82. doi: 10.2174/0115734099274797231205055827.
5
Convergent QSAR Models for the Prediction of Cruzain Inhibitors.
ACS Omega. 2023 Oct 13;8(42):38961-38982. doi: 10.1021/acsomega.3c03376. eCollection 2023 Oct 24.
6
Targeting Cysteine Proteases and their Inhibitors to Combat Trypanosomiasis.
Curr Med Chem. 2024;31(16):2135-2169. doi: 10.2174/0929867330666230619160509.
7
Screening the Pathogen Box to Discover and Characterize New Cruzain and CatL Inhibitors.
Pathogens. 2023 Feb 4;12(2):251. doi: 10.3390/pathogens12020251.
8
Antiparasitic Activities of Compounds Isolated from Strain Discovered in Northcentral Nigeria.
Antibiotics (Basel). 2023 Jan 6;12(1):109. doi: 10.3390/antibiotics12010109.
9
De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies.
Adv Appl Bioinform Chem. 2022 Aug 1;15:29-41. doi: 10.2147/AABC.S361626. eCollection 2022.
10
De Novo Molecular Design of Caspase-6 Inhibitors by a GRU-Based Recurrent Neural Network Combined with a Transfer Learning Approach.
Pharmaceuticals (Basel). 2021 Nov 30;14(12):1249. doi: 10.3390/ph14121249.
本文引用的文献
1
Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease.
J Med Chem. 2010 Jan 14;53(1):37-51. doi: 10.1021/jm901070c.
2
Rational modification of a candidate cancer drug for use against Chagas disease.
J Med Chem. 2009 Mar 26;52(6):1639-47. doi: 10.1021/jm801313t.
3
RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model.
PLoS Negl Trop Dis. 2008 Sep 24;2(9):e298. doi: 10.1371/journal.pntd.0000298.
4
Compound Management for Quantitative High-Throughput Screening.
JALA Charlottesv Va. 2008 Apr;13(2):79-89. doi: 10.1016/j.jala.2007.12.004.
5
Identification of a new class of nonpeptidic inhibitors of cruzain.
J Am Chem Soc. 2008 May 21;130(20):6404-10. doi: 10.1021/ja710254m. Epub 2008 Apr 25.
6
Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB.
J Med Chem. 2008 Feb 14;51(3):545-52. doi: 10.1021/jm070760l. Epub 2008 Jan 4.
7
A cysteine protease inhibitor cures Chagas' disease in an immunodeficient-mouse model of infection.
Antimicrob Agents Chemother. 2007 Nov;51(11):3932-9. doi: 10.1128/AAC.00436-07. Epub 2007 Aug 13.
8
A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds.
Bioorg Med Chem Lett. 2007 Feb 15;17(4):998-1002. doi: 10.1016/j.bmcl.2006.11.044. Epub 2006 Nov 17.
9
Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.
Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8. doi: 10.1073/pnas.0604348103. Epub 2006 Jul 24.
10
A cysteine protease inhibitor protects dogs from cardiac damage during infection by Trypanosoma cruzi.
Antimicrob Agents Chemother. 2005 Dec;49(12):5160-1. doi: 10.1128/AAC.49.12.5160-5161.2005.
Zotero 插件