Deokhee Kang
Chemical Biologist / Cultural Writer / Jazz Composer & Pianist
Peptides already serve as a promising modality, yet much of their potential remains hidden.
Scheme 1. Intracellular screening of cleavage-resistant cyclic peptide inhibitors [1].
Intracellular platforms provide a physiologically relevant environment and enable activity-based, counter-selective screening, in contrast to conventional affinity-based display techniques, which often yield idiosyncratic side effects. To address these limitations, we developed a yeast-based intracellular screening platform for cyclic peptide inhibitors, aiming to improve proteolytic resistance as well as serum and thermal stability. To overcome intrinsic constraints of intracellular platforms, we incorporated genetic code expansion to introduce functional unnatural amino acids targeting the catalytic cavity of the enzyme. This approach enables the identification of promising hits even from relatively small genetically encoded libraries. Yeast two-hybrid, split intein, and genetic code expansion techniques were strategically integrated to realize this platform.
Scheme 2. Protease-activated restricted interaction peptide platform [2].
Stoichiometric inhibition of enzymes does not always achieve a broad therapeutic window. Instead of directly inhibiting enzymatic activity, we leveraged enzyme activity to improve therapeutic outcomes. Restricted Interaction Peptides are designed to be activated upon cleavage by disease-associated proteases, enabling interaction with cell membranes and enhancing local retention of the payload. Using this strategy, we achieved selective delivery of cytotoxic agents and radioisotopes, resulting in improved tumor localization and prolonged tumor retention compared to conventional stoichiometric binders.
I’ve taken a broad and exploratory approach to peptide drug discovery, working across diverse strategies to tackle complex problems.
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