Discovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2

Overview

Journal Chembiochem

Specialty Biochemistry

Date 2021 Apr 16

PMID 33861519

Citations 4

Authors

Emmanuel K Toroitich

Anthony M Ciancone

Heung Sik Hahm

Skylar M Brodowski

Adam H Libby

Ku-Lung Hsu

Affiliations

Soon will be listed here.

Abstract

Sulfonyl-triazoles have emerged as a new reactive group for covalent modification of tyrosine sites on proteins through sulfur-triazole exchange (SuTEx) chemistry. The extent to which this sulfur electrophile can be tuned for developing ligands with cellular activity remains largely underexplored. Here, we performed fragment-based ligand discovery in live cells to identify SuTEx compounds capable of liganding tyrosine sites on diverse protein targets. We verified our quantitative chemical proteomic findings by demonstrating concentration-dependent activity of SuTEx ligands, but not inactive counterparts, against recombinant protein targets directly in live cells. Our structure-activity relationship studies identified the SuTEx ligand HHS-0701 as a cell-active inhibitor capable of blocking prostaglandin reductase 2 (PTGR2) biochemical activity.

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References

Ban H, Gavrilyuk J, Barbas 3rd C . Tyrosine bioconjugation through aqueous ene-type reactions: a click-like reaction for tyrosine. J Am Chem Soc. 2010; 132(5):1523-5. DOI: 10.1021/ja909062q. View

Carter A, Kraemer O, Zwick M, Mueller-Fahrnow A, Arrowsmith C, Edwards A . Target 2035: probing the human proteome. Drug Discov Today. 2019; 24(11):2111-2115. DOI: 10.1016/j.drudis.2019.06.020. View

Chen W, Dong J, Plate L, Mortenson D, Brighty G, Li S . Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue. J Am Chem Soc. 2016; 138(23):7353-64. PMC: 4909538. DOI: 10.1021/jacs.6b02960. View

Hacker S, Backus K, Lazear M, Forli S, Correia B, Cravatt B . Global profiling of lysine reactivity and ligandability in the human proteome. Nat Chem. 2017; 9(12):1181-1190. PMC: 5726523. DOI: 10.1038/nchem.2826. View

Mann M . Functional and quantitative proteomics using SILAC. Nat Rev Mol Cell Biol. 2006; 7(12):952-8. DOI: 10.1038/nrm2067. View

Yoo E, Stokes B, de Jong H, Vanaerschot M, Kumar T, Lawrence N . Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. J Am Chem Soc. 2018; 140(36):11424-11437. PMC: 6407133. DOI: 10.1021/jacs.8b06656. View

Bern M, Kil Y, Becker C . Byonic: advanced peptide and protein identification software. Curr Protoc Bioinformatics. 2012; Chapter 13:13.20.1-13.20.14. PMC: 3545648. DOI: 10.1002/0471250953.bi1320s40. View

Scott D, Coyne A, Hudson S, Abell C . Fragment-based approaches in drug discovery and chemical biology. Biochemistry. 2012; 51(25):4990-5003. DOI: 10.1021/bi3005126. View

Narayanan A, Jones L . Sulfonyl fluorides as privileged warheads in chemical biology. Chem Sci. 2017; 6(5):2650-2659. PMC: 5489032. DOI: 10.1039/c5sc00408j. View

10.

Erlanson D, Fesik S, Hubbard R, Jahnke W, Jhoti H . Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov. 2016; 15(9):605-619. DOI: 10.1038/nrd.2016.109. View

11.

Simon G, Cravatt B . Activity-based proteomics of enzyme superfamilies: serine hydrolases as a case study. J Biol Chem. 2010; 285(15):11051-5. PMC: 2856978. DOI: 10.1074/jbc.R109.097600. View

12.

Weerapana E, Wang C, Simon G, Richter F, Khare S, Dillon M . Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature. 2010; 468(7325):790-5. PMC: 3058684. DOI: 10.1038/nature09472. View

13.

Vinogradova E, Zhang X, Remillard D, Lazar D, Suciu R, Wang Y . An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells. Cell. 2020; 182(4):1009-1026.e29. PMC: 7775622. DOI: 10.1016/j.cell.2020.07.001. View

14.

Cravatt B, Wright A, Kozarich J . Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu Rev Biochem. 2008; 77:383-414. DOI: 10.1146/annurev.biochem.75.101304.124125. View

15.

Bergeron A, DAstous M, Timm D, Tanguay R . Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1. J Biol Chem. 2001; 276(18):15225-31. DOI: 10.1074/jbc.M009341200. View

16.

Keller L, Babin B, Lakemeyer M, Bogyo M . Activity-based protein profiling in bacteria: Applications for identification of therapeutic targets and characterization of microbial communities. Curr Opin Chem Biol. 2019; 54:45-53. PMC: 7131876. DOI: 10.1016/j.cbpa.2019.10.007. View

17.

Huang T, Hosseinibarkooie S, Borne A, Granade M, Brulet J, Harris T . Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes. Chem Sci. 2021; 12(9):3295-3307. PMC: 8179411. DOI: 10.1039/d0sc06623k. View

18.

Bradshaw J, McFarland J, Paavilainen V, Bisconte A, Tam D, Phan V . Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem Biol. 2015; 11(7):525-31. PMC: 4472506. DOI: 10.1038/nchembio.1817. View

19.

Munos B . Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov. 2009; 8(12):959-68. DOI: 10.1038/nrd2961. View

20.

Zhao Q, Ouyang X, Wan X, Gajiwala K, Kath J, Jones L . Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes. J Am Chem Soc. 2017; 139(2):680-685. PMC: 5858558. DOI: 10.1021/jacs.6b08536. View