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Dithiol amino acids can structurally shape and enhance the ligand-binding properties of polypeptides.

Chen S, Gopalakrishnan R, Schaer T, Marger F, Hovius R, Bertrand D, Pojer F, Heinis C
Nat Chem 6 1009-16 (2014)
Related entries: 2moa, 4os1, 4os2, 4os4, 4os6, 4os7

Cited: 33 times
EuropePMC logo PMID: 25343607

Abstract

The disulfide bonds that form between two cysteine residues are important in defining and rigidifying the structures of proteins and peptides. In polypeptides containing multiple cysteine residues, disulfide isomerization can lead to multiple products with different biological activities. Here, we describe the development of a dithiol amino acid (Dtaa) that can form two disulfide bridges at a single amino acid site. Application of Dtaas to a serine protease inhibitor and a nicotinic acetylcholine receptor inhibitor that contain disulfide constraints enhanced their inhibitory activities 40- and 7.6-fold, respectively. X-ray crystallographic and NMR structure analysis show that the peptide ligands containing Dtaas have retained their native tertiary structures. We furthermore show that replacement of two cysteines by Dtaas can avoid the formation of disulfide bond isomers. With these properties, Dtaas are likely to have broad application in the rational design or directed evolution of peptides and proteins with high activity and stability.

Reviews citing this publication (10)

  1. Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes. Pelay-Gimeno M, Glas A, Koch O, Grossmann TN. Angew Chem Int Ed Engl 54 8896-8927 (2015)
  2. New Modalities for Challenging Targets in Drug Discovery. Valeur E, Guéret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, Grossmann TN, Plowright AT. Angew Chem Int Ed Engl 56 10294-10323 (2017)
  3. Peptide and protein nanoparticle conjugates: versatile platforms for biomedical applications. Spicer CD, Jumeaux C, Gupta B, Stevens MM. Chem Soc Rev 47 3574-3620 (2018)
  4. Nicotinic acetylcholine receptor inhibitors derived from snake and snail venoms. Dutertre S, Nicke A, Tsetlin VI. Neuropharmacology 127 196-223 (2017)
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  6. Therapeutics targeting the fibrinolytic system. Lin H, Xu L, Yu S, Hong W, Huang M, Xu P. Exp Mol Med 52 367-379 (2020)
  7. Recent Advances Toward the Discovery of Drug-Like Peptides De novo. Goldflam M, Ullman CG. Front Chem 3 69 (2015)
  8. Structural Principles in the Development of Cyclic Peptidic Enzyme Inhibitors. Xu P, Andreasen PA, Huang M. Int J Biol Sci 13 1222-1233 (2017)
  9. Assessing Methodologies to Synthesize α-Sulfenylated Carbonyl Compounds by Green Chemistry Metrics. Margalef J, Samec JSM. ChemSusChem 14 808-823 (2021)
  10. Biosynthetic Strategies for Macrocyclic Peptides. Wang W, Khojasteh SC, Su D. Molecules 26 3338 (2021)

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  1. Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy. Peraro L, Zou Z, Makwana KM, Cummings AE, Ball HL, Yu H, Lin YS, Levine B, Kritzer JA. J Am Chem Soc 139 7792-7802 (2017)
  2. Small cyclic agonists of iron regulatory hormone hepcidin. Chua K, Fung E, Micewicz ED, Ganz T, Nemeth E, Ruchala P. Bioorg Med Chem Lett 25 4961-4969 (2015)
  3. Conformational Restriction of Peptides Using Dithiol Bis-Alkylation. Peraro L, Siegert TR, Kritzer JA. Methods Enzymol 580 303-332 (2016)
  4. Stereoselective and Divergent Construction of β-Thiolated/Selenolated Amino Acids via Photoredox-Catalyzed Asymmetric Giese Reaction. Yin H, Zheng M, Chen H, Wang S, Zhou Q, Zhang Q, Wang P. J Am Chem Soc 142 14201-14209 (2020)
  5. Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics. Vishwanatha TM, Bergamaschi E, Dömling A. Org Lett 19 3195-3198 (2017)
  6. Precisely Regulated and Efficient Locking of Linear Peptides into Stable Multicyclic Topologies through a One-Pot Reaction. Liu W, Zheng Y, Kong X, Heinis C, Zhao Y, Wu C. Angew Chem Int Ed Engl 56 4458-4463 (2017)
  7. Artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers. Zheng Y, Li Z, Ren J, Liu W, Wu Y, Zhao Y, Wu C. Chem Sci 8 2547-2552 (2017)
  8. Role of CysI-CysIII Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors. Tabassum N, Tae HS, Jia X, Kaas Q, Jiang T, Adams DJ, Yu R. ACS Omega 2 4621-4631 (2017)
  9. Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation. Micewicz ED, Sharma S, Waring AJ, Luong HT, McBride WH, Ruchala P. Int J Pept Res Ther 22 67-81 (2016)
  10. A phage display-based strategy for the de novo creation of disulfide-constrained and isomer-free bicyclic peptide affinity reagents. Zha M, Lin P, Yao H, Zhao Y, Wu C. Chem Commun (Camb) 54 4029-4032 (2018)
  11. Identification of highly selective covalent inhibitors by phage display. Chen S, Lovell S, Lee S, Fellner M, Mace PD, Bogyo M. Nat Biotechnol 39 490-498 (2021)
  12. Development of antithrombotic nanoconjugate blocking integrin α2β1-collagen interactions. Zhang C, Zhang L, Zhang Y, Sun N, Jiang S, Fujihara TJ, Sun Y. Sci Rep 6 26292 (2016)
  13. Editorial Editorial: Chemical Design and Biomedical Applications of Disulfide-rich Peptides: Challenges and Opportunities. Imhof D, Roy D, Albericio F. Front Chem 8 586377 (2020)
  14. Iodine-promoted stereoselective amidosulfenylation of electron-deficient alkynes. Xiao F, Wang D, Yuan S, Huang H, Deng GJ. RSC Adv 8 23319-23322 (2018)
  15. Ordered and Isomerically Stable Bicyclic Peptide Scaffolds Constrained through Cystine Bridges and Proline Turns. Lin P, Yao H, Zha J, Zhao Y, Wu C. Chembiochem 20 1514-1518 (2019)
  16. Synthesis of Reusable Silica Nanosphere-Supported Pt(IV) Complex for Formation of Disulfide Bonds in Peptides. Hou X, Zhao X, Zhang Y, Han A, Huo S, Shen S. Molecules 22 (2017)
  17. The Symmetric Tetravalent Sulfhydryl-Specific Linker NATBA Facilitates a Combinatorial "Tool Kit" Strategy for Phage Display-Based Selection of Functionalized Bicyclic Peptides. Ernst C, Sindlinger J, Schwarzer D, Koch P, Boeckler FM. ACS Omega 3 12361-12368 (2018)
  18. An evolution-inspired strategy to design disulfide-rich peptides tolerant to extensive sequence manipulation. Zha J, Li J, Fan S, Duan Z, Zhao Y, Wu C. Chem Sci 12 11464-11472 (2021)
  19. Autophagy inducing cyclic peptides constructed by methionine alkylation. Qin X, Shi X, Tu L, Ma Y, Zhou Z, Zhao R, Zhan M, Yin F, Li Z. Chem Commun (Camb) 55 4198-4201 (2019)
  20. Detection of Phenylarsine Oxide in Drinking Water Using an Impedimetric Electrochemical Sensor with Gelatin-Based Solid Electrolyte Enriched with Mercaptoethanol: A Novel Prospective Green Biosensor Methodology. Keser K, Soylu MÇ. ACS Omega 7 43111-43121 (2022)
  21. Oligophenyls with Multiple Disulfide Bridges as Higher Homologues of Dibenzo[c,e][1,2]dithiin: Synthesis and Application in Lithium-Ion Batteries. Sonnenschein C, Ender CP, Wang F, Schollmeyer D, Feng X, Narita A, Müllen K. Chemistry 26 8007-8011 (2020)
  22. Peptidic Sulfhydryl for Interfacing Nanocrystals and Subsequent Sensing of SARS-CoV-2 Protease. Jin Z, Yeung J, Zhou J, Cheng Y, Li Y, Mantri Y, He T, Yim W, Xu M, Wu Z, Fajtova P, Creyer MN, Moore C, Fu L, Penny WF, O'Donoghue AJ, Jokerst JV. Chem Mater 34 1259-1268 (2022)
  23. Structure-guided design of CPPC-paired disulfide-rich peptide libraries for ligand and drug discovery. Wu Y, Fan S, Dong M, Li J, Kong C, Zhuang J, Meng X, Lu S, Zhao Y, Wu C. Chem Sci 13 7780-7789 (2022)


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