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Published on 26.02.2025
For the generation of ADCs and other protein derivatives, cysteine to maleimide conjugation (a variety of the Michael addition) is a frequently used approach. However, the resulting succinimide-thioether is prone to hydrolysis by retro-Michael addition, which affects long-term stability of the conjugate.
Discover our novel compound nitroveratryl-oxycarbonyl maleimido-aminoethyl beta-alanine (RL-8710) – a photo-caged crosslinker allowing for the construction of stable thioether conjugates!
Structure of RL-8710: The nitroveratryloxycarbonyl moiety (Nvoc, orange) protects the secondary amine and may be removed by irradiation with UV-light. The maleimido moiety which conjugates to thiols is depicted in green. The building block may be integrated into a polypeptide chain by Fmoc/tBu SPPS via activation of the carboxy group (see figure below).
The nitrogen in beta position to the maleimido function can be deprotected by irradiation with ultraviolet light of 365 nm. The resulting free secondary amine catalyzes the ring-opening reaction of the maleimide. It is still under discussion whether it acts as a base in proximity to the carbonyl functions of succinimide or exerts an electron withdrawing effect. Either way, the succinimide-thioether opens to a succinic monoamide with a stabilized thioether. As light source, UV-LEDs may be used; with a 30W lamp, the reaction has been reported to complete within minutes.
Use case: Labeling of an antibody with a payload, using the maleimide RL-8710 which is attached to the N-terminus of the load by SPPS. The maleimide reacts with an accessible thiol on the antibody. The resulting succinimide-thioether is stabilized by a ring-opening reaction (conversion of the succinimide to a succinic monoamide) which is induced by the photochemical removal of the DMNB protective group. Of course, the scope of RL-8710 is not limited to the labeling of antibodies; virtually any molecule providing one or more thiol(s) may be coupled.
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References:
On-Demand Thio-Succinimide Hydrolysis for the Assembly of Stable Protein–Protein Conjugates; A. V. Vasco, R. J. Taylor, Y. Méndez, G. J. L. Bernardes; J. Am. Chem. Soc. 2024; 146(30): 20709–20719. https://doi.org/10.1021/jacs.4c03721
Diverse reactivity of maleimides in polymer science and beyond; B. E. Kirkpatrick, K. S. Anseth, T. S. Hebner; Polymer Int. 2024. https://doi.org/10.1002/pi.6715
