Conformational Switch of a Peptide Provides a Novel Strategy to Design Peptide Loaded Porous Organic Polymer for Pyroptosis Pathway Mediated Cancer Therapy

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2024-10, Vol.20 (42), p.e2402953-n/a
• Main Authors: Mishra, Snehasis, Sannigrahi, Achinta, Ruidas, Santu, Chatterjee, Sujan, Roy, Kamalesh, Misra, Deblina, Maity, Barun Kumar, Paul, Rabindranath, Ghosh, Chandan Kumar, Saha, Krishna Das, Bhaumik, Asim, Chattopadhyay, Krishnananda
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; cancer; Cancer therapies; Cell death; Cell Line, Tumor; Cell membranes; Chemical synthesis; conformational switch; Humans; membrane pore formation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; peptide; Peptides; Peptides - chemistry; Peptides - pharmacology; Phloroglucinol; Phospholipids; Polymers; Polymers - chemistry; Porosity; porous organic polymer; pyroptosis; Pyroptosis - drug effects
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202402953

While peptide‐based drug development is extensively explored, this strategy has limitations due to rapid excretion from the body (or shorter half‐life in the body) and vulnerability to protease‐mediated degradation. To overcome these limitations, a novel strategy for the development of a peptide‐based anticancer agent is introduced, utilizing the conformation switch property of a chameleon sequence stretch (PEP1) derived from a mycobacterium secretory protein, MPT63. The selected peptide is then loaded into a new porous organic polymer (PG‐DFC‐POP) synthesized using phloroglucinol and a cresol derivative via a condensation reaction to deliver the peptide selectively to cancer cells. Utilizing ensemble and single‐molecule approaches, this peptide undergoes a transition from a disordered to an alpha‐helical conformation, triggered by the acidic environment within cancer cells that is demonstrated. This adopted alpha‐helical conformation resulted in the formation of proteolysis‐resistant oligomers, which showed efficient membrane pore‐forming activity selectively for negatively charged phospholipids accumulated in cancer cell membranes. The experimental results demonstrated that the peptide‐loaded PG‐DFC‐POP‐PEP1 exhibited significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway, which is established by monitoring numerous associated events starting from lysosome membrane damage to GSDMD‐induced cell membrane demolition. This novel conformational switch‐based drug design strategy is believed to have great potential in endogenous environment‐responsive cancer therapy and the development of future drug candidates to mitigate cancers. Cancer cell death via the Pyroptosis pathway is facilitated by PEP1 encapsulated within the PG‐DFC‐POP nanomaterial, employing a conformational switch strategy as activated by acidic pH conditions. Conformational switch‐driven oligomerization of PEP1 modulates numerous downstream processes leading to programmed cell death of cancer cells.