Application of Click Chemistry Towards The Synthesis of Bifunctional Stapled Peptides
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Cocktail therapies in cancer treatment are proven to be effective. Compared with cocktail therapies, fused bifunctional peptides are more predictable for their pharmacokinetic properties and potentially synergistic. Here, we report the synthesis of the bifunctional stapled peptides using click chemistry. We demonstrate that both a BH3 stapled peptide-based Bcl-2 inhibitor and a tubulin-binding cemadotin analog showed potent cell-killing activity in Mcl-1 over-expressing K562 cells. EC 50 of the co-treatment of the stapled BH3 peptide and the cemadotin analog was 0.44 μM, indicating higher potency than single treatment. We anticipate that the fused stapled BH3-cemadotin peptides would exhibit higher cell-killing activity and more predictable pharmacokinetic properties in cancer cells.