Rational design of reversible and irreversible cysteine sulfenic acid-targeted linear C-nucleophiles

Abstract

Concerns about off-target effects has motivated the development of reversible covalent inhibition strategies for targeting cysteine. However, such strategies have not been reported for the unique cysteine oxoform, sulfenic acid. Herein, we have designed and identified linear C-nucleophiles that react selectively with cysteine sulfenic acid. The resulting thioether adducts exhibit reversibility ranging from minutes to days under reducing conditions, showing the feasibility of tuning C-nucleophile reactivity across a wide range of time scales.

Fig. 1

Structure and reaction of various classes of linear C-nucleophiles with sulfenic acid 2.

Fig. 2

(A) Strategy for rational design of linear C-nucleophiles exhibiting superior reactivity with Cys-SOH. (B) Structure and putative reaction sties of curcumin (11) and tofacitinib (12) towards sulfenic acid 2.

Fig. 3

Stability of thioethers 13 - 18 under reducing conditions.

Fig. 4

Stability of protein-S-Nu thioether bonds under reducing conditions. (a) Alkyne-functionlized irreversible and reversible C-nucleophiles; (b) Gel-based reactivity profiling of irreversible and reversible C-nucleophiles in HeLa cell lysate.