Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9096
Title: Synthesis of Well-Defined Heparan Sulfate Proteoglycan Mimetics to Study Cell Surface Engineering and Drug Delivery
Authors: KIKKERI, RAGHAVENDRA
ANAND, SAURABH
Dept. of Chemistry
20172016
Keywords: Heparan Sulfate
Proteoglycan Mimics
Cell Surface Engineering
Drug Delivery
Voltage Gated Ion Potassium Ion Channek
Issue Date: Sep-2024
Citation: 281
Abstract: Heparan sulfate proteoglycans (HSPGs) are essential components of the extracellular matrix and cell surfaces, playing pivotal roles in various biological processes. Composed of a core protein with covalently attached heparan sulfate chains, HSPGs are crucial for cell-cell interactions, signaling regulation, and the organization of the extracellular environment. The synthesis of proteoglycan mimetics involves sophisticated chemical and biochemical strategies aimed at replicating the intricate structures and functions of natural proteoglycans, such as heparan sulfate proteoglycans (HSPGs). Li et al. employ synthetic organic chemistry to design molecules that mimic the glycosaminoglycan chains (e.g., heparan sulfate, chondroitin sulfate) and the core proteins to which they attach. These mimetics are engineered to exhibit specific biological activities, such as binding to growth factors, cytokines, or cell surface receptors, similar to natural HSPGs. Bioconjugation techniques are crucial for linking synthetic glycosaminoglycan chains to appropriate protein or peptide scaffolds, ensuring structural and functional mimicry. The synthesis of proteoglycan mimetics holds significant promise for applications in regenerative medicine, drug delivery systems, and biomaterial development, where precise control over biological interactions is essential for therapeutic efficacy (Sugahara et al., 2015). Chapter 1 highlights that proteoglycans are vital components of the extracellular matrix and plasma membrane, featuring core proteins linked to glycosaminoglycans (GAGs). These complexes store and deliver growth factors, thereby regulating cellular processes. Current research is focused on creating simplified proteoglycan mimics to influence biological activities, especially in areas such as stem cell research, neural plasticity, viral inhibition, cancer biology, and biomarker development. Chapter 2 discusses the significance of synthesizing monodisperse, precise multivalent, fluorescently labeled peptide backbones using cholesterol as a template for creating proteoglycan mimetics (PGs). Heparan sulfate proteoglycans (HSPGs) play key roles in various biological functions due to their complex structures, which include varying uronic acids and sulfation patterns. This complexity necessitates the precise synthesis of proteoglycan mimetics to better understand their specific biological functions. Chapter 3 explores how membrane-bound HSPGs act as receptors for growth factors and influence endocytosis. The study highlights how specific sulfation and uronic acid compositions in heparan sulfate impact cell dynamics and the internalization of HSPG mimetics. For example, 3-O-sulfated iduronic acid (PG@ID-2) facilitates faster endocytosis and affects cell migration and proliferation, underscoring the importance of sulfation patterns. Chapter 4 explains the importance of developing stable membrane probes for studying cell dynamics. The microheterogeneity of heparan sulfate on fluorescent neo-proteoglycans provides a new platform for probing cellular functions. Highly sulfated heparan sulfate ligands with L-iduronic acid (PG@ID-6) show prolonged presence on the plasma membrane, which is useful for mapping basement membranes and enhancing imaging techniques. Chapter 5 highlights the critical role of the extracellular matrix, particularly heparan sulfate (HS), in regulating interactions with drugs and toxins. The structural diversity of HS influences how cisplatin binds to it, with a preference for L-iduronic acid. A proteoglycan mimic containing IdoA (P-I12) demonstrates selective toxicity in cancer cells, thereby enhancing drug delivery and suggesting potential applications in targeted therapies. Chapter 6 discusses how voltage-gated ion channels are modulated by glycosaminoglycan proteoglycans. The study reveals that the sulfation of heparan sulfate and the sialic acid linkages on proteoglycan mimetics affect glycocalyx remodeling and Kv2.1 channel behavior. High sulfation and flexible sialylation lead to prolonged cell membrane persistence and altered ion channel activity, offering insights for the development of therapeutic probes.
URI: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9096
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