Recapitulating the Binding Affinity of Nrf2 for KEAP1 in a Cyclic Heptapeptide, Guided by NMR, X-ray Crystallography, and Machine Learning

Ortet, P; Muellers, S.; Viarengo-Baker, L.; Streu, K.; Szymczyna, B.; Beeler, A.; Allen, K.; Whitty, A.

doi:10.1021/jacs.0c09799

Recapitulating the Binding Affinity of Nrf2 for KEAP1 in a Cyclic Heptapeptide, Guided by NMR, X-ray Crystallography, and Machine Learning

Journal Article · Sat Jan 01 04:00:00 EST 2022 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.0c09799· OSTI ID:1783957

Ortet, P; Muellers, S.; Viarengo-Baker, L.; Streu, K.; Szymczyna, B.; Beeler, A.; Allen, K.; Whitty, A.

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: ~OTHER

DOE Contract Number:: SC0012704

OSTI ID:: 1783957

Report Number(s):: BNL-221488-2021-JACI

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 10 Vol. 143; ISSN 0002-7863

Country of Publication:: United States

Language:: English

References (61)

Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction Hancock, Rowena; Bertrand, Hélène C.; Tsujita, Tadayuki Free Radical Biology and Medicine, Vol. 52, Issue 2 https://doi.org/10.1016/j.freeradbiomed.2011.10.486	journal	January 2012
Getting in Shape: Controlling Peptide Bioactivity and Bioavailability Using Conformational Constraints Bock, Jonathan E.; Gavenonis, Jason; Kritzer, Joshua A. ACS Chemical Biology, Vol. 8, Issue 3 https://doi.org/10.1021/cb300515u	journal	November 2012
Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors Cee, Victor J.; Chavez, Frank; Herberich, Bradley ACS Medicinal Chemistry Letters, Vol. 7, Issue 4 https://doi.org/10.1021/acsmedchemlett.5b00403	journal	February 2016
Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable Nielsen, Daniel S.; Hoang, Huy N.; Lohman, Rink-Jan Angewandte Chemie International Edition, Vol. 53, Issue 45 https://doi.org/10.1002/anie.201405364	journal	September 2014
Role of the Keap1/Nrf2 pathway in neurodegenerative diseases: Nrf2 and neurodegenerative diseases Yamazaki, Hiromi; Tanji, Kunikazu; Wakabayashi, Koichi Pathology International, Vol. 65, Issue 5 https://doi.org/10.1111/pin.12261	journal	February 2015
Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads Huang, Yifang; Strobel, Eric D.; Ho, Chih Y. Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 10 https://doi.org/10.1016/j.bmcl.2010.03.097	journal	May 2010
Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges Vinogradov, Alexander A.; Yin, Yizhen; Suga, Hiroaki Journal of the American Chemical Society, Vol. 141, Issue 10 https://doi.org/10.1021/jacs.8b13178	journal	February 2019
Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa Acta Pharmaceutica Sinica B, Vol. 5, Issue 4 https://doi.org/10.1016/j.apsb.2015.05.008	journal	July 2015
Binding Efficiency of Protein–Protein Complexes Day, Eric S.; Cote, Shaun M.; Whitty, Adrian Biochemistry, Vol. 51, Issue 45 https://doi.org/10.1021/bi301039t	journal	November 2012
Enzymatic Transition States and Drug Design Schramm, Vern L. Chemical Reviews, Vol. 118, Issue 22 https://doi.org/10.1021/acs.chemrev.8b00369	journal	October 2018
A theoretical foundation for the PLS algorithm Lorber, Avraham; Wangen, Lawrence E.; Kowalski, Bruce R. Journal of Chemometrics, Vol. 1, Issue 1 https://doi.org/10.1002/cem.1180010105	journal	January 1987
Orally Absorbed Cyclic Peptides Nielsen, Daniel S.; Shepherd, Nicholas E.; Xu, Weijun Chemical Reviews, Vol. 117, Issue 12 https://doi.org/10.1021/acs.chemrev.6b00838	journal	May 2017
Crystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experiments Hörer, Stefan; Reinert, Dirk; Ostmann, Katja Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 69, Issue 6 https://doi.org/10.1107/S174430911301124X	journal	May 2013
Critical Effect of Peptide Cyclization on the Potency of Peptide Inhibitors against Dengue Virus NS2B-NS3 Protease Xu, Shaoqiong; Li, Hua; Shao, Xiaoxia Journal of Medicinal Chemistry, Vol. 55, Issue 15 https://doi.org/10.1021/jm300655h	journal	July 2012
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases Cuadrado, Antonio; Rojo, Ana I.; Wells, Geoffrey Nature Reviews Drug Discovery, Vol. 18, Issue 4 https://doi.org/10.1038/s41573-018-0008-x	journal	January 2019
Improved WATERGATE Pulse Sequences for Solvent Suppression in NMR Spectroscopy Liu, Maili; Mao, Xi-an; Ye, Chaohui Journal of Magnetic Resonance, Vol. 132, Issue 1 https://doi.org/10.1006/jmre.1998.1405	journal	May 1998
Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model Tong, Kit I.; Katoh, Yasutake; Kusunoki, Hideki Molecular and Cellular Biology, Vol. 26, Issue 8 https://doi.org/10.1128/MCB.26.8.2887-2900.2006	journal	April 2006
Binding Affinity Prediction for Protein–Ligand Complexes Based on β Contacts and B Factor Liu, Qian; Kwoh, Chee Keong; Li, Jinyan Journal of Chemical Information and Modeling, Vol. 53, Issue 11 https://doi.org/10.1021/ci400450h	journal	November 2013
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties? Giordanetto, Fabrizio; Kihlberg, Jan Journal of Medicinal Chemistry, Vol. 57, Issue 2 https://doi.org/10.1021/jm400887j	journal	September 2013
PLS-regression: a basic tool of chemometrics Wold, Svante; Sjöström, Michael; Eriksson, Lennart Chemometrics and Intelligent Laboratory Systems, Vol. 58, Issue 2 https://doi.org/10.1016/S0169-7439(01)00155-1	journal	October 2001
Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions Piotto, Martial; Saudek, Vladimir; Sklenář, Vladimir Journal of Biomolecular NMR, Vol. 2, Issue 6 https://doi.org/10.1007/BF02192855	journal	November 1992
Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency Lu, Meng-Chen; Jiao, Qiong; Liu, Tian European Journal of Medicinal Chemistry, Vol. 143 https://doi.org/10.1016/j.ejmech.2017.10.052	journal	January 2018
A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity Tran, Kim T.; Pallesen, Jakob S.; Solbak, Sara M. Ø. Journal of Medicinal Chemistry, Vol. 62, Issue 17 https://doi.org/10.1021/acs.jmedchem.9b00723	journal	August 2019
The exploration of macrocycles for drug discovery — an underexploited structural class Driggers, Edward M.; Hale, Stephen P.; Lee, Jinbo Nature Reviews Drug Discovery, Vol. 7, Issue 7 https://doi.org/10.1038/nrd2590	journal	July 2008
Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction Steel, Richard J.; O'Connell, Maria A.; Searcey, Mark Bioorganic & Medicinal Chemistry Letters, Vol. 28, Issue 16 https://doi.org/10.1016/j.bmcl.2018.03.003	journal	September 2018
Going Out on a Limb: Delineating The Effects of β-Branching, N -Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues Bockus, Andrew T.; Schwochert, Joshua A.; Pye, Cameron R. Journal of Medicinal Chemistry, Vol. 58, Issue 18 https://doi.org/10.1021/acs.jmedchem.5b00919	journal	September 2015
Rapid Flow-Based Peptide Synthesis Simon, Mark D.; Heider, Patrick L.; Adamo, Andrea ChemBioChem, Vol. 15, Issue 5 https://doi.org/10.1002/cbic.201300796	journal	March 2014
MOrPH-PhD: An Integrated Phage Display Platform for the Discovery of Functional Genetically Encoded Peptide Macrocycles Owens, Andrew E.; Iannuzzelli, Jacob A.; Gu, Yu ACS Central Science, Vol. 6, Issue 3 https://doi.org/10.1021/acscentsci.9b00927	journal	February 2020
Binding thermodynamics and kinetics guided optimization of potent Keap1–Nrf2 peptide inhibitors Lu, Meng-Chen; Chen, Zhi-Yun; Wang, Ya-Lou RSC Advances, Vol. 5, Issue 105 https://doi.org/10.1039/C5RA16262A	journal	January 2015
Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2 Eggler, A. L.; Liu, G.; Pezzuto, J. M. Proceedings of the National Academy of Sciences, Vol. 102, Issue 29 https://doi.org/10.1073/pnas.0502402102	journal	July 2005
Comprehensive Experimental and Computational Analysis of Binding Energy Hot Spots at the NF-κB Essential Modulator/IKKβ Protein–Protein Interface Golden, Mary S.; Cote, Shaun M.; Sayeg, Marianna Journal of the American Chemical Society, Vol. 135, Issue 16 https://doi.org/10.1021/ja400914z	journal	April 2013
How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets Doak, Bradley C.; Zheng, Jie; Dobritzsch, Doreen Journal of Medicinal Chemistry, Vol. 59, Issue 6 https://doi.org/10.1021/acs.jmedchem.5b01286	journal	October 2015
Macrocycles in new drug discovery Mallinson, Jamie; Collins, Ian Future Medicinal Chemistry, Vol. 4, Issue 11 https://doi.org/10.4155/fmc.12.93	journal	July 2012
Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery Whitty, Adrian; Viarengo, Lauren A.; Zhong, Mengqi Organic & Biomolecular Chemistry, Vol. 15, Issue 37 https://doi.org/10.1039/C7OB00056A	journal	January 2017
The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases Tu, Wenjun; Wang, Hong; Li, Song Aging and disease, Vol. 10, Issue 3 https://doi.org/10.14336/AD.2018.0513	journal	January 2019
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
Crystal Structures of Protein-Bound Cyclic Peptides Malde, Alpeshkumar K.; Hill, Timothy A.; Iyer, Abishek Chemical Reviews, Vol. 119, Issue 17 https://doi.org/10.1021/acs.chemrev.8b00807	journal	May 2019
Macrocycles: lessons from the distant past, recent developments, and future directions Yudin, Andrei K. Chemical Science, Vol. 6, Issue 1 https://doi.org/10.1039/C4SC03089C	journal	January 2015
Discovery of Kinase Spectrum Selective Macrocycle (16 E )-14-Methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a Potent Inhibitor of Cyclin Dependent Kinases (CDKs), Janus Kinase 2 (JAK2), and Fms-like Tyrosine Kinase-3 (FLT3) for the Treatment of Cancer William, Anthony D.; Lee, Angeline C. -H.; Goh, Kee Chuan Journal of Medicinal Chemistry, Vol. 55, Issue 1 https://doi.org/10.1021/jm201112g	journal	December 2011
Interaction Energetics and Druggability of the Protein–Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2) Zhong, Mengqi; Lynch, Andrew; Muellers, Samantha N. Biochemistry, Vol. 59, Issue 4 https://doi.org/10.1021/acs.biochem.9b00943	journal	December 2019
Industrial PLS model variable selection using moving window variable importance in projection Lu, Bo; Castillo, Ivan; Chiang, Leo Chemometrics and Intelligent Laboratory Systems, Vol. 135 https://doi.org/10.1016/j.chemolab.2014.03.020	journal	July 2014
Modified Peptide Inhibitors of the Keap1–Nrf2 Protein–Protein Interaction Incorporating Unnatural Amino Acids Georgakopoulos, Nikolaos D.; Talapatra, Sandeep K.; Gatliff, Jemma ChemBioChem, Vol. 19, Issue 17 https://doi.org/10.1002/cbic.201800170	journal	July 2018
LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery Laskowski, Roman A.; Swindells, Mark B. Journal of Chemical Information and Modeling, Vol. 51, Issue 10 https://doi.org/10.1021/ci200227u	journal	October 2011
Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.1 ^3,7 .1 ^9,13 ]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene Macrocycles Breslin, Henry J.; Lane, Brandon M.; Ott, Gregory R. Journal of Medicinal Chemistry, Vol. 55, Issue 1 https://doi.org/10.1021/jm201333e	journal	December 2011
Tools and rules for macrocycles Heinis, Christian Nature Chemical Biology, Vol. 10, Issue 9 https://doi.org/10.1038/nchembio.1605	journal	July 2014
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex Zhang, Donna D.; Lo, Shih-Ching; Cross, Janet V. Molecular and Cellular Biology, Vol. 24, Issue 24 https://doi.org/10.1128/MCB.24.24.10941-10953.2004	journal	December 2004
Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon Journal of Medicinal Chemistry, Vol. 57, Issue 11 https://doi.org/10.1021/jm500261q	journal	December 2013
New Frontiers in Druggability Kozakov, Dima; Hall, David R.; Napoleon, Raeanne L. Journal of Medicinal Chemistry, Vol. 58, Issue 23 https://doi.org/10.1021/acs.jmedchem.5b00586	journal	August 2015
Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products Bockus, Andrew T.; Lexa, Katrina W.; Pye, Cameron R. Journal of Medicinal Chemistry, Vol. 58, Issue 11 https://doi.org/10.1021/acs.jmedchem.5b00128	journal	May 2015
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery Davies, Thomas G.; Wixted, William E.; Coyle, Joseph E. Journal of Medicinal Chemistry, Vol. 59, Issue 8 https://doi.org/10.1021/acs.jmedchem.6b00228	journal	April 2016
How proteins bind macrocycles Villar, Elizabeth A.; Beglov, Dmitri; Chennamadhavuni, Spandan Nature Chemical Biology, Vol. 10, Issue 9 https://doi.org/10.1038/nchembio.1584	journal	July 2014
Molecular Properties That Influence the Oral Bioavailability of Drug Candidates Veber, Daniel F.; Johnson, Stephen R.; Cheng, Hung-Yuan Journal of Medicinal Chemistry, Vol. 45, Issue 12 https://doi.org/10.1021/jm020017n	journal	June 2002
Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling Lo, Shih-Ching; Li, Xuchu; Henzl, Michael T. The EMBO Journal, Vol. 25, Issue 15 https://doi.org/10.1038/sj.emboj.7601243	journal	August 2006
Small molecules inhibiting Keap1–Nrf2 protein–protein interactions: a novel approach to activate Nrf2 function Zhuang, Chunlin; Wu, Zhongli; Xing, Chengguo MedChemComm, Vol. 8, Issue 2 https://doi.org/10.1039/C6MD00500D	journal	January 2017
Macrocyclic Inhibitors of β-Secretase: Functional Activity in an Animal Model Stachel, Shawn J.; Coburn, Craig A.; Sankaranarayanan, Sethu Journal of Medicinal Chemistry, Vol. 49, Issue 21 https://doi.org/10.1021/jm060884i	journal	October 2006
Kinetic Analyses of Keap1-Nrf2 Interaction and Determination of the Minimal Nrf2 Peptide Sequence Required for Keap1 Binding Using Surface Plasmon Resonance: Kinetic Analyses of Keap1-Nrf2 Peptide Interactions Chen, Yu; Inoyama, Daigo; Kong, Ah-Ng Tony Chemical Biology & Drug Design, Vol. 78, Issue 6 https://doi.org/10.1111/j.1747-0285.2011.01240.x	journal	October 2011
Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein–Protein Interaction Zhou, Haibin; Liu, Liu; Huang, Jing Journal of Medicinal Chemistry, Vol. 56, Issue 3 https://doi.org/10.1021/jm3015298	journal	January 2013
Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response Tong, Kit I.; Padmanabhan, Balasundaram; Kobayashi, Akira Molecular and Cellular Biology, Vol. 27, Issue 21 https://doi.org/10.1128/MCB.00753-07	journal	November 2007
Principal component analysis Wold, Svante; Esbensen, Kim; Geladi, Paul Chemometrics and Intelligent Laboratory Systems, Vol. 2, Issue 1-3 https://doi.org/10.1016/0169-7439(87)80084-9	journal	August 1987
Passive Membrane Permeability in Cyclic Peptomer Scaffolds Is Robust to Extensive Variation in Side Chain Functionality and Backbone Geometry Furukawa, Akihiro; Townsend, Chad E.; Schwochert, Joshua Journal of Medicinal Chemistry, Vol. 59, Issue 20 https://doi.org/10.1021/acs.jmedchem.6b01246	journal	October 2016
Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery Marsault, Eric; Peterson, Mark L. Journal of Medicinal Chemistry, Vol. 54, Issue 7 https://doi.org/10.1021/jm1012374	journal	April 2011

Similar Records

The Effects of CapZ Peptide (TRTK-12) Binding to S100B___Ca2+ as Examined by NMR and X-ray Crystallography

Journal Article · Wed Oct 31 00:00:00 EDT 2012 · J. Mol. Biol. 396:1227,2010 · OSTI ID:1054139

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding

Journal Article · Tue Nov 01 00:00:00 EDT 2016 · Biochimica et Biophysica Acta - General Subjects · OSTI ID:1347780

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding

Journal Article · Mon Oct 31 20:00:00 EDT 2016 · Biochimica et Biophysica Acta - General Subjects · OSTI ID:1396468

Related Subjects

99 GENERAL AND MISCELLANEOUS

Recapitulating the Binding Affinity of Nrf2 for KEAP1 in a Cyclic Heptapeptide, Guided by NMR, X-ray Crystallography, and Machine Learning

Citation Formats

References (61)

Similar Records

Related Subjects