Molecular Engineering and Self-Assembly of Bioactive Short Peptides for Next-Generation Therapeutic Strategies

Sarkar, Sandip (2026) Molecular Engineering and Self-Assembly of Bioactive Short Peptides for Next-Generation Therapeutic Strategies. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sandip Sarkar (20RS049)) 20RS049.pdf - Submitted Version Restricted to Repository staff only Download (22MB)

Abstract

The development of effective therapeutic strategies for complex diseases such as cancer and ischemic stroke remains challenging due to their multifactorial nature, involving oxidative stress, inflammation, metabolic imbalance, and metal-ion dysregulation. Conventional therapies often suffer from poor specificity, limited bioavailability, systemic toxicity, and inadequate control over drug release. These challenges are particularly significant for biotherapeutics, including peptides and biomacromolecules, which are prone to rapid degradation and inefficient intracellular delivery. Therefore, there is a pressing need for advanced platforms that enhance stability, targeting, and therapeutic efficacy while enabling stimuli-responsive interventions. In this thesis, we report the rational design of supramolecular systems integrating enzyme responsiveness, self-assembly, targeted delivery, coacervation, and metal-ion regulation. These systems exploit dynamic non-covalent interactions to create adaptable therapeutic platforms capable of responding to pathological cues with high precision. A calix[4]arene-based host–guest system (CAOPP) was developed to stabilize peptide therapeutics and enable mitochondrial targeting. The resulting pseudorotaxane complexes undergo alkaline phosphatase (ALP)-triggered activation in cancer cells, leading to in situ self-assembly, mitochondrial dysfunction, and selective apoptosis, demonstrating significant tumour inhibition in vivo. Furthermore, enzyme-responsive coacervate vesicles derived from sequence-defined peptides (Biotin–SR) were engineered as biomimetic delivery systems. These structures encapsulate biomolecules such as glucose oxidase (GOx) and undergo ALP-triggered disassembly, releasing cargo to generate oxidative–nitrosative stress and induce apoptosis. Their effectiveness in 3D tumour spheroids and in vivo models highlights coacervation as a programmable platform for localized delivery. Additionally, a multifunctional small molecule, Ben-O-Gua, was developed for ischemic stroke. Its self-assembled nanosheets enable efficient Fe/Cu chelation, suppressing reactive oxygen species and inhibiting cuproptosis and ferroptosis, resulting in significant neuroprotection in vivo. Overall, this work establishes a versatile supramolecular framework that enhances the stability, specificity, and efficacy of biotherapeutics, offering new directions for precision therapeutics.

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