Conformational switch of a peptide provides a novel strategy to design peptide loaded porous organic polymer for Pyroptosis pathway mediated cancer therapy
While peptide-based drug development is now extensively explored, this strategy does have limitations, which come from their rapid excretion from the body (or shorter half-life in the body), and vulnerability to protease-mediated degradation. To overcome these limitations, here we introduce a novel strategy for the development of a peptide-based anticancer agent using the conformation switch property of a chameleon sequence stretch, which we derived from a mycobacterium secretory protein, MPT63. Then, we loaded this peptide in a new porous organic polymer (PG-DFC-POP) synthesized using phloroglucinol and acresolderivative via condensation reaction for delivering the peptide selectively to the cancer cells. Employing an ensemble and single molecule approaches, we demonstrate that this peptide undergoes a disordered to alpha-helical conformational transition, which is triggered by a low pH environment inside cancer cells. This adopted alpha-helical conformation results in the formation of proteolysis-resistant oligomers, which show efficient membrane pore-forming activity selectively for negatively charged phospholipid which is accumulated in cancer cell membrane. Our in vitro and in vivo experimental results demonstrate that the peptide-loaded nanomaterial PG-DFC-POP-PEP 1 exhibits significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway that is confirmed by monitoring numerous associated events starting from lysosome membrane damage to GSDMD-induced cell membrane demolition. We believe that this novel conformational switch-based drug design strategy has great potential in endogenous environment-responsive cancer therapy and the development of future drug candidates to mitigate cancers.