Small-Molecule Inhibitors of the m7G-RNA Writer METTL1

被引：14

作者：

Nai, Francesco ^{[1
]}

Espinoza, Maria Paula Flores ^{[1
]}

Invernizzi, Annalisa ^{[1
]}

Vargas-Rosales, Pablo Andres ^{[1
]}

Bobileva, Olga ^{[2
]}

Herok, Marcin ^{[1
]}

Caflisch, Amedeo ^{[1
]}

机构：

[1] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland

[2] Latvian Inst Organ Synth, LV-1006 Riga, Latvia

来源：

ACS BIO & MED CHEM AU | 2023年 / 4卷 / 02期

基金：

瑞士国家科学基金会;

关键词：

epitranscriptomics; m7Gwriter; X-ray crystallography; enzymatic assay; docking; MD simulation; drug discovery; RNA; METHYLATION; DYNAMICS; MODEL;

D O I：

10.1021/acsbiomedchemau.3c00030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40-300 mu M. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate S-adenosyl methionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85 A.

引用

页码：100 / 110

页数：11

共 54 条

[1] Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers [J].

Abraham, Mark James ;

Murtola, Teemu ;

Schulz, Roland ;

Páll, Szilárd ;

Smith, Jeremy C. ;

Hess, Berk ;

Lindah, Erik .

SoftwareX, 2015, 1-2 :19-25

[2] Towards automated crystallographic structure refinement with phenix.refine [J].

Afonine, Pavel V. ;

Grosse-Kunstleve, Ralf W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Moriarty, Nigel W. ;

Mustyakimov, Marat ;

Terwilliger, Thomas C. ;

Urzhumtsev, Alexandre ;

Zwart, Peter H. ;

Adams, Paul D. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2012, 68 :352-367

[3] Rapid tRNA decay can result from lack of nonessential modifications [J].

Alexandrov, A ;

Chernyakov, I ;

Gu, WF ;

Hiley, SL ;

Hughes, TR ;

Grayhack, EJ ;

Phizicky, EM .

MOLECULAR CELL, 2006, 21 (01) :87-96

[4] Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer [J].

Bedi, Rajiv K. ;

Huang Danzhi ;

Eberle, Stefanie A. ;

Wiedmer, Lars ;

Sledz, Pawel ;

Caflisch, Amedeo .

CHEMMEDCHEM, 2020, 15 (09) :744-748

[5] 3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors [J].

Bobileva, Olga ;

Bobrovs, Raitis ;

Sirma, Evelina Elva ;

Kanepe, Iveta ;

Bula, Anna L. ;

Patetko, Liene ;

Ramata-Stunda, Anna ;

Grinberga, Solveiga ;

Jirgensons, Aigars ;

Jaudzems, Kristaps .

MOLECULES, 2023, 28 (02)

[6] Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate [J].

Bobileva, Olga ;

Bobrovs, Raitis ;

Kanepe, Iveta ;

Patetko, Liene ;

Kalnins, Gints ;

Sisovs, Mihails ;

Bula, Anna L. ;

Grinberga, Solveiga ;

Boroduskis, Martins ;

Ramata-Stunda, Anna ;

Rostoks, Nils ;

Jirgensons, Aigars ;

Tars, Kaspars ;

Jaudzems, Kristaps .

ACS MEDICINAL CHEMISTRY LETTERS, 2021, 12 (07) :1102-1107

[7] Put the Pedal to the METTL1: Adding Internal m7G Increases mRNA Translation Efficiency and Augments miRNA Processing [J].

Boulias, Konstantinos ;

Greer, Eric Lieberman .

MOLECULAR CELL, 2019, 74 (06) :1105-1107

[8] Mutations in WDR4 as a new cause of Galloway-Mowat syndrome [J].

Braun, Daniela A. ;

Shril, Shirlee ;

Sinha, Aditi ;

Schneider, Ronen ;

Tan, Weizhen ;

Ashraf, Shazia ;

Hermle, Tobias ;

Jobst-Schwan, Tilman ;

Widmeier, Eugen ;

Majmundar, Amar J. ;

Daga, Ankana ;

Warejko, Jillian K. ;

Nakayama, Makiko ;

Schapiro, David ;

Chen, Jing ;

Airik, Merlin ;

Rao, Jia ;

Schmidt, Johanna Magdalena ;

Hoogstraten, Charlotte A. ;

Hugo, Hannah ;

Meena, Jitendra ;

Lek, Monkol ;

Laricchia, Kristen M. ;

Bagga, Arvind ;

Hildebrandt, Friedhelm .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2018, 176 (11) :2460-2465

[9] Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer [J].

Campeanu, Ion John ;

Jiang, Yuanyuan ;

Liu, Lanxin ;

Pilecki, Maksymilian ;

Najor, Alvina ;

Cobani, Era ;

Manning, Morenci ;

Zhang, Xiaohong Mary ;

Yang, Zeng-Quan .

SCIENTIFIC REPORTS, 2021, 11 (01)

[10] Novel roles of METTL1/WDR4 in tumor via m7G methylation [J].

Cheng, Wenli ;

Gao, Aili ;

Lin, Hui ;

Zhang, Wenjuan .

MOLECULAR THERAPY ONCOLYTICS, 2022, 26 :27-34

← 1 2 3 4 5 6 →