PotM: A Lysine Multitool Building Block

Iris Biotech introduces Fmoc-L-Lys(4-N3-Z)-OH (FAA8830), a multifunctional lysine building block that can be introduced by SPPS. Its azido group facilitates multiple applications. Firstly, azido groups are useful handles for several bioorthogonal ligation reactions, such as the Staudinger ligation, as well as copper-catalyzed and strain-promoted azide-alkyne cycloadditions. Due to their spectral characteristics, azides also lend themselves to being employed as infrared (IR) or Raman probes. Moreover, aryl-azides may also be used as photocrosslinkers. Upon irradiation with UV light, they readily form highly stabilized nitrenes, which are the nitrogen analogues of carbenes (isoelectronic) and react in a comparable fashion. Lastly, the para-azido benzyloxycarbonyl group may be cleaved in a bioorthogonal fashion either by a 1,3-dipolar cycloaddition (trans-cyclooctene, acrolein), or by reduction. Reducing agents can either be endogenous (e.g. hydrogen sulfide, NADPH), or exogeneous (DTT, TCEP).

This uncaging reaction is highly useful for activating a prodrug (e.g. a peptide). As one example, a targeted prodrug activation in cancer cells has been shown that relied on the uncaging with the endogenous reagent acrolein.  Since acrolein is frequently overproduced by cancer cells, the prodrug activation takes place predominantly in cancerous tissue.

To sum up, Fmoc-L-Lys(4-N3-Z)-OH (FAA8830) is useful for the following applications:

• Bioorthogonal ligations (Staudinger, CuAAC, SPAAC)

• Infrared probe (IR and Raman)

• Photocrosslinking (photoaffinity capture)

• Bioorthogonal unmasking of lysine by e.g. 1,3-dipolar cycloaddition or reduction (by exogeneous or endogenous reducing agents)

Coming soon: Iris Biotech will shortly introduce the free amine H-L-Lys(4-N3-Z)-OH that can be introduced into proteins by genetic code expansion. Be sure to check our newsletters in the upcoming weeks!

References:

Targeted 1,3-dipolar cycloaddition with acrolein for cancer prodrug activation; A. R. Pradipta, P. Ahmadi, K. Terashima, K. Muguruma, M. Fujii, T. Ichino, S. Maeda and K. Tanaka; Chem. Sci. 2021; 12: 5438-5449. https://doi.org/10.1039/d0sc06083f

Phosphine-Activated Lysine Analogues for Fast Chemical Control of Protein Subcellular Localization and Protein SUMOylation; J. S. Wesalo, J. Luo, K. Morihiro, J. Liu and A. Deiters; Chembiochem 2020; 21: 141-148. https://doi.org/10.1002/cbic.201900464

Structural Basis for Genetic-Code Expansion with Bulky Lysine Derivatives by an Engineered Pyrrolysyl-tRNA Synthetase; T. Yanagisawa, M. Kuratani, E. Seki, N. Hino, K. Sakamoto and S. Yokoyama; Cell Chem Biol 2019; 26: 936-949 e13. https://doi.org/10.1016/j.chembiol.2019.03.008

A genetically encoded multifunctional unnatural amino acid for versatile protein manipulations in living cells; Y. Ge, X. Fan and P. R. Chen; Chem. Sci. 2016; 7: 7055-7060. https://doi.org/10.1039/c6sc02615j