Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 12;13(43):12808-12817.
doi: 10.1039/d2sc04558c. eCollection 2022 Nov 9.

Tyrosine bioconjugation with hypervalent iodine

Nina Declas  1 , John R J Maynard  2 , Laure Menin  3 , Natalia Gasilova  3 , Sebastian Götze  4 , Jakob L Sprague  5 , Pierre Stallforth  4 , Stefan Matile  2 , Jerome Waser  1
Affiliations

Tyrosine bioconjugation with hypervalent iodine

Nina Declas et al. Chem Sci. .

Erratum in

  • Correction: Tyrosine bioconjugation with hypervalent iodine.
    Declas N, Maynard JRJ, Menin L, Gasilova N, Götze S, Sprague JL, Stallforth P, Matile S, Waser J. Declas N, et al. Chem Sci. 2022 Dec 15;14(2):393-394. doi: 10.1039/d2sc90252d. eCollection 2023 Jan 4. Chem Sci. 2022. PMID: 36687350 Free PMC article.

Abstract

Hypervalent iodine reagents have recently emerged as powerful tools for late-stage peptide and protein functionalization. Herein we report a tyrosine bioconjugation methodology for the introduction of hypervalent iodine onto biomolecules under physiological conditions. Tyrosine residues were engaged in a selective addition onto the alkynyl bond of ethynylbenziodoxolones (EBX), resulting in stable vinylbenziodoxolones (VBX) bioconjugates. The methodology was successfully applied to peptides and proteins and tolerated all other nucleophilic residues, with the exception of cysteine. The generated VBX were further functionalized by palladium-catalyzed cross-coupling and azide-alkyne cycloaddition reactions. The method could be successfully used to modify bioactive natural products and native streptavidin to enable thiol-mediated cellular uptake.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. (a) Amino acids targeted for bioconjugation. (b) Reported tyrosine bioconjugation methodologies. (c) Development of a tyrosine-selective bioconjugation method with hypervalent iodine reagents.
Scheme 2
Scheme 2. (a) Scope of tetramers on 20.0 μmol. (b) Scope of bioactive peptides on 1.0 μmol or 1.0 mg. Tyr* = Tyr modified with EBX. HPLC-MS yields are given, determined as indicated in Scheme 1. aIsolated yield. bObtained as a 1 : 2 mixture with 4.
Scheme 3
Scheme 3. Functionalization of proteins and antibody. Conditions A: Protein (10.0 nmol), N3-EBX 2a (10.0 equiv), 100 μM in Tris buffer (100 mM, pH 9.0), 72 h. Conditions B: Protein (10.0 nmol), N3-EBX 2a (50.0 equiv), 100 μM in Tris buffer (100 mM, pH 9.0), 24 h. Conditions C: Trastuzumab (1.0 nmol), N3-EBX 2a (5.0 equiv), 10 μM in Tris buffer (100 mM, pH 9.0), 4 h. The ratio indicated corresponds to the signal intensity of all the functionalized products mass over the sum of the intensities of all other products with a threshold of 5% intensity. aDenaturing conditions: Tris buffer (100 mM, pH 9.0, 6.0 M GdmHCl).
Scheme 4
Scheme 4. Scope of EBX reagents on β-casomorphin human peptide 1r and jagaricin (1w). HPLC-MS yields are given as indicated in Scheme 1.
Scheme 5
Scheme 5. (a) SPAAC functionalization on O-VBX 3a, 20.0 μmol. (b) One-pot two-step labeling/SPAAC functionalization of peptides. Reaction on vasopressin (1o) (0.762 μmol) and β-casomorphin human peptide (1r) (1.0 μmol). (c) Suzuki–Miyaura functionalization on O-VBX 3a, 20.0 μmol. (d) One-pot two-step labeling/Suzuki–Miyaura functionalization of β-casomorphin human peptide (1.0 μmol). (e) One-pot three-step labeling/Suzuki–Miyaura/SPAAC functionalization of β-casomorphin human peptide (1.0 μmol). aIsolated yield is given. bHPLC-UV yield over two steps is given. c10.0 equiv of Pd and 20% of DMSO were used. The reaction time was 4 hours. dHPLC-UV yield over three steps is given.
Fig. 1
Fig. 1. Cellular uptake of streptavidin using O-VBX. (a) Schematic representations of fluorescent biotin-streptavidin complexes used in uptake studies. (b) Relative fluorescence intensities of live HeLa MZ cells in SDCM images following incubation with 10 μM N3, AspA, or CTO for 6 h. Images of HeLa cells incubated with 18 N3 (c), 19 AspA (d), and 20 CTO (e) at 10 μM for 6 h (Blue = Hoechst 33342, Red = TAMRA). Scale bars: 150 μm. Brightness and contrast were adjusted equally in all images.
See this image and copyright information in PMC

References

    1. Fosgerau K. Hoffmann T. Drug Discovery Today. 2015;20:122. doi: 10.1016/j.drudis.2014.10.003. - DOI - PubMed
    2. Hu Q.-Y. Berti F. Adamo R. Chem. Soc. Rev. 2016;45:1691–1719. doi: 10.1039/C4CS00388H. - DOI - PubMed
    3. Gunnoo S. B. Madder A. Org. Biomol. Chem. 2016;14:8002–8013. doi: 10.1039/C6OB00808A. - DOI - PubMed
    4. Lau J. L. Dunn M. K. Bioorg. Med. Chem. 2018;26:2700–2707. doi: 10.1016/j.bmc.2017.06.052. - DOI - PubMed
    1. Spicer C. D. Davis B. G. Nat. Commun. 2014;5:4740. doi: 10.1038/ncomms5740. - DOI - PubMed
    2. Koniev O. Wagner A. Chem. Soc. Rev. 2015;44:5495–5551. doi: 10.1039/C5CS00048C. - DOI - PubMed
    3. Boutureira O. Bernardes G. J. L. Chem. Rev. 2015;115:2174–2195. doi: 10.1021/cr500399p. - DOI - PubMed
    4. Hoyt E. A. Cal P. M. S. D. Oliveira B. L. Bernardes G. J. L. Nat. Rev. Chem. 2019;3:147–171. doi: 10.1038/s41570-019-0079-1. - DOI
    5. Tamura T. Hamachi I. J. Am. Chem. Soc. 2019;141:2782–2799. doi: 10.1021/jacs.8b11747. - DOI - PubMed
    6. Boto A. González C. C. Hernández D. Romero-Estudillo I. Saavedra C. J. Org. Chem. Front. 2021;8:6720–6759. doi: 10.1039/D1QO00892G. - DOI
    7. Walsh S. J. Bargh J. D. Dannheim F. M. Hanby A. R. Seki H. Counsell A. J. Ou X. Fowler E. Ashman N. Takada Y. et al. Chem. Soc. Rev. 2021;50:1305–1353. doi: 10.1039/D0CS00310G. - DOI - PubMed
    8. Sornay C. Vaur V. Wagner A. Chaubet G. R. Soc. Open Sci. 2022;9:211563. doi: 10.1098/rsos.211563. - DOI - PMC - PubMed
    1. Sevier C. S. Kaiser C. A. Nat. Rev. Mol. Cell Biol. 2002;3:836–847. doi: 10.1038/nrm954. - DOI - PubMed
    1. Lin S. Yang X. Jia S. Weeks A. M. Hornsby M. Lee P. S. Nichiporuk R. V. Iavarone A. T. Wells J. A. Toste F. D. et al. Science. 2017;355:597–602. doi: 10.1126/science.aal3316. - DOI - PMC - PubMed
    2. Taylor M. T. Nelson J. E. Suero M. G. Gaunt M. J. Nature. 2018;562:563–568. doi: 10.1038/s41586-018-0608-y. - DOI - PMC - PubMed
    3. Kim J. Li B. X. Huang R. Y.-C. Qiao J. X. Ewing W. R. MacMillan D. W. C. J. Am. Chem. Soc. 2020;142:21260–21266. doi: 10.1021/jacs.0c09926. - DOI - PMC - PubMed
    1. Antos J. M. Francis M. B. J. Am. Chem. Soc. 2004;126:10256–10257. doi: 10.1021/ja047272c. - DOI - PubMed
    2. Seki Y. Ishiyama T. Sasaki D. Abe J. Sohma Y. Oisaki K. Kanai M. J. Am. Chem. Soc. 2016;138:10798–10801. doi: 10.1021/jacs.6b06692. - DOI - PubMed
    3. Tower S. J. Hetcher W. J. Myers T. E. Kuehl N. J. Taylor M. T. J. Am. Chem. Soc. 2020;142:9112–9118. doi: 10.1021/jacs.0c03039. - DOI - PMC - PubMed