Molecular Engineering of Peptide-Nanomaterial Hybrids for Biocatalytic and Therapeutic Applications

Chatterjee, Atin (2026) Molecular Engineering of Peptide-Nanomaterial Hybrids for Biocatalytic and Therapeutic Applications. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Atin Chatterjee (20RS047)) 20RS047.pdf - Submitted Version Restricted to Repository staff only Download (19MB)

Abstract

The rational design of multifunctional therapeutics that integrate molecular recognition, photochemical responsiveness, and catalytic activity for site-specific treatment remains a cornerstone of modern chemical biology. This work converges small-molecule–peptide conjugates with nanomaterial–photosensitizer hybrids to develop smart molecular platforms for targeted biocatalysis and protein-directed therapy. First, an N-stapled peptide-Ru(II) conjugate (Ru-NAP) was engineered for the treatment of triple-negative breast carcinoma (TNBC). By leveraging the high binding affinity (Ka: 6.8х10⁶ M⁻¹) of Ru-NAP toward β-tubulin and its fibrillar morphology, we achieved targeted microtubule disruption and light-activated singlet oxygen generation (¹O₂) resulting in synergistic chemo–photodynamic efficacy. To address the limitations of oxygen-dependent therapies, a complementary heterojunction (CBB/RuPS) was developed by integrating a Bi-based perovskite (Cs₃Bi₂Br₉) with a Ru(II)-polypyridyl (RuPS) complex. This CBB/RuPS hybrid facilitates ultrafast charge transfer (200-300 ps) to drive tandem redox biocatalysis via a Type I electron-transfer pathway. This approach effectively disrupts the electron transport chain and ensures sustained reactive oxygen species (ROS) generation, even within hypoxic tumor microenvironments. Extending design principles to neurodegenerative disorders, a supramolecular intervention was designed to target Aβ-42 aggregation in Alzheimer’s disease. The crown ether peptide conjugate, 18C6-LV-PEG, utilizes a dual-recognition strategy engaging the ¹⁷LVFF²⁰ motifwhile simultaneously clamping the Lys¹⁶ residue. This synergistic engagement suppresses hydrophobic interactions, inhibits oligomerization, and promotes the disassembly of mature fibrils, thereby restoring neuronal connectivity and cognitive function in vivo. Together, these studies establish a unified framework for programmable, spatiotemporally controlled therapeutics, bridging molecular-material hybrids with supramolecular assemblies to advance next-generation medicine.

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