Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter January 21, 2022

Photochemical protein modification in complex biological environments: recent advances and considerations for future chemical methods development

  • Michael T. Taylor ORCID logo EMAIL logo
From the journal Biological Chemistry


The development of organic reactions that covalently modify biological matter in complex biological mixtures has become an invaluable asset in drug discovery. Out of the techniques developed to date, optically controlled chemistries are of particular utility owing to both the spatiotemporal control afforded by optical control as well as the impressive array of transformations that are driven by the highly reactive intermediates generated upon excitation. This minireview discusses recent advances in the development of photochemical reactions for use in complex mixtures and highlights key considerations for future photochemical reaction designs.

Corresponding author: Michael T. Taylor, Department of Chemistry, University of Wyoming, 1000 E. University Ave., Laramie, WY 82071, USA, E-mail:

Funding source: NIGMS funded Sensory Biology COBRE

Award Identifier / Grant number: P20 GM121310


We thank the NIGMS-funded Wyoming Sensory Biology COBRE program (P20 GM121310) for support.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This review was supported by NIGMS funded Sensory Biology COBRE program (P20 GM121310).

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.


Bach, K., Beerkens, B.L.H., Zanon, P.R.A., and Hacker, S.M. (2020). Light-activatable, 2,5-disubstituted tetrazoles for the proteome-wide profiling of aspartates and glutamates in living bacteria. ACS Cent. Sci. 6: 546–554, in Google Scholar PubMed PubMed Central

Beard, S., Hauser, J.R., Walko, M., George, R.M., Wilson, A.J., and Bon, R.S. (2019). Photocatalytic proximity labelling of MCL-1 by a BH3 ligand. Commun. Chem. 2: Article number: 133, in Google Scholar PubMed PubMed Central

Botecchia, C. and Noël, T. (2019). Photocatalytic modification of amino acids, peptides, and proteins. Chem. Eur. J. 25: 26–42.10.1002/chem.201803074Search in Google Scholar PubMed PubMed Central

Conway, L.P., Jadhav, A.M., Homan, R.A., Li, W., Rubiano, J.S., Hawkins, R., Lawrence, R.M., and Parker, C.G. (2021). Evaluation of fully-functionalized diazirine tags for chemical proteomic applications. Chem. Sci. 12: 7839–7847, in Google Scholar PubMed PubMed Central

Cravatt, B.F., Wright, A.T., and Kozarich, J.W. (2008). Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem. 77: 383–414, in Google Scholar PubMed

Dai, S.-Y. and Yang, D. (2020). A visible and near-infrared light activatable diazocoumarin probe for fluorogenic protein labeling in living cells. J. Am. Chem. Soc. 142: 17156–17166, in Google Scholar PubMed

Das, J. (2011). Aliphatic diazirines as photoaffinity probes for proteins: recent developments. Chem. Rev. 111: 4405–4417, in Google Scholar PubMed

Fancy, D.A. and Kodadek, T. (1999). Chemistry for the analysis of protein–protein interactions: rapid and efficient cross-linking triggered by long wavelength light. Proc. Natl. Acad. Sci. U.S.A. 96: 6020–6024, in Google Scholar PubMed PubMed Central

Geri, J.B., Oakley, J.V., Reyes-Robles, T., Wang, T., McCarver, S.J., White, C.H., Rodriguez-Rivera, F.P., Parker, D.L.Jr., Hett, E.C., Fadeyi, O.O., et al.. (2020). Microenvironment mapping via Dexter energy transfer on immune cells. Science 367: 1091–1097, in Google Scholar PubMed PubMed Central

Geurink, P.P., Prely, L.M., van der Marel, G.A., Bischoff, R., and Overkleeft, H.S. (2012). Photoaffinity labeling in activity-based protein profiling. Top. Curr. Chem. 324: 85–113, in Google Scholar PubMed

Jamieson, C. and Livingstone, K. (2020). The generation of nitrile imine derivatives. In: The nitrile imine 1,3-dipole. Cham: Springer.10.1007/978-3-030-43481-6_2Search in Google Scholar

Kim, K., Fancy, D.A., Carney, D., and Kodadek, T. (1999). Photoinduced protein cross-linking mediated by palladium porphyrins. J. Am. Chem. Soc. 121: 11896–11897, in Google Scholar

Kotzyba-Hibert, F., Kapfer, I., and Goeldner, M. (1995). Recent trends in photoaffinity labeling. Angew. Chem. Int. Ed. 34: 1296–1312, in Google Scholar

Mix, K.A., Lomax, J.E., and Raines, R.T. (2017). Cytosolic delivery of proteins by bioreversible esterification. J. Am. Chem. Soc. 139: 14396–14398, in Google Scholar PubMed PubMed Central

O’Brien, J.G.K., Jemas, A., Asare-Okai, P.N., Am Ende, C.W., and Fox, J.M. (2020). Probing the mechanism of photoaffinity labeling by dalkyldiazirines through bioorthogonal capture of diazoalkanes. Org. Lett. 22: 9415–9420, in Google Scholar PubMed PubMed Central

Ramil, C.P. and Lin, Q. (2014). Photoclick chemistry: a fluorogenic light-triggered in vivo ligation reaction. Curr. Opin. Chem. Biol. 21: 89–95, in Google Scholar PubMed PubMed Central

Sato, S., Morita, K., and Nakamura, H. (2015). Regulation of target protein knockdown and labeling using ligand-directed Ru(bpy)3 photocatalyst. Bioconjugate Chem. 26: 250–256.10.1021/bc500518tSearch in Google Scholar PubMed

Sato, S. and Nakamura, H. (2013). Ligand-directed selective protein modification based on local single-electron-transfer catalysis. Angew. Chem. Int. Ed. 52: 8681–8684, in Google Scholar PubMed

Smith, E. and Collins, I. (2015). Photoaffinity labeling in target- and binding-site identification. Future Med. Chem. 7: 159–183, in Google Scholar PubMed PubMed Central

Spradlin, J.N., Zhang, E., and Nomura, D.K. (2021). Reimagining druggability using chemoproteomic platforms. Acc. Chem. Res. 54: 1801–1813, in Google Scholar PubMed

Stacey, O.J. and Pope, S.J.A. (2013). New Avenues in the design and potential application of metal complexes for photodynamic therapy. RSC Adv. 3: 25550–25564, in Google Scholar

Tamura, T., Takato, M., Shiono, K., and Hamachi, I. (2020). Development of a photoactivatable proximity labeling method for the identification of nuclear proteins. Chem. Lett. 49: 145–148, in Google Scholar

Tan, Y.H., Liu, M., Nolting, B., Go, J.G., Gervay-Hague, J., and Liu, G.-Y. (2008). A nanoengineering approach for investigation and regulation of protein immobilization. ACS Nano 11: 2374–2384, in Google Scholar PubMed PubMed Central

Wang, H., Zhang, Y., Zeng, K., Qiang, J., Cao, Y., Li, Y., Fang, Y., Zhang, Y., and Chen, Y. (2021). Selective mitochondrial protein labeling enabled by biocompatible photocatalytic reactions inside live cells. JACS Au 1: 1066–1075, in Google Scholar PubMed PubMed Central

West, A.V., Mucipinto, G., Wu, H.Y., Huang, A.C., Labenski, M.T., Jones, L.H., and Woo, C.M. (2021). Labeling preferences of diazirines with protein biomolecules. J. Am. Chem. Soc. 143: 6691–6700, in Google Scholar PubMed

Wood, P.M. (1988). The potential diagram for oxygen at pH 7. Biochem. J. 253: 287–289, in Google Scholar PubMed PubMed Central

Zhao, S., Dai, J., Hu, M., Liu, C., Meng, R., Liu, X., Wang, C., and Luo, T. (2016). Photo-induced coupling reactions of tetrazoles with carboxylic acids in aqueous solution: application in protein labelling. Chem. Commun. 52: 4702–4705, in Google Scholar PubMed

Received: 2021-08-20
Accepted: 2022-01-12
Published Online: 2022-01-21
Published in Print: 2022-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 27.5.2023 from
Scroll to top button