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Michael addition reaction between cysteinyl thiols and maleimides to form thio-maleimide linkages, is extensively used for labeling proteins with fluorophores, affinity tags, polyethylene glycol moieties and drug molecules for a diverse range of applications. In particular, the tremendous success of antibody-drug conjugates (ADCs) generated by appending drug molecules to antibodies by employing this chemistry has had a transformative impact on cancer therapy. Consequently, recent reports on the susceptibility of these linkages to undergo thiol exchange-mediated breakdown in the physiological milieu are extremely alarming1,2. In my talk, I shall describe two approaches that my research group has developed to overcome this problem3,4. One of these approaches is based on our discovery that unlike conventional maleimides, exocyclic olefinic maleimides form thiol exchange-resistant conjugates and hence are preferable for stable thiol bioconjugation3. In another approach, we have rationally designed a photoactivable maleimide derivative that after bioconjugation can be irradiated with UV light to trigger rapid thio-maleimide ring hydrolysis to form stable conjugates4. I shall also discuss our recently developed strategy of installing exocyclic olefinic maleimide at the N-terminus of proteins and employing this chemistry for labelling bacterial cell surfaces5.
References:
1) B. Q. Shen et al., Nat. Biotechnol. 2012, 30, 184–189.
2) R. P. Lyon et al., Nat. Biotechnol. 2014, 32, 1059–1062.
3) D. Kalia* et al., Angew. Chem. Int. Ed. 2016, 55, 1432–1435.
4) D. Kalia* et al., Angew. Chem. Int. Ed. 2017, 56, 1885–1889.
5) D. Kalia* et al., Manuscript in preparation.
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