SYNTHETIC MIMICS OF MAMMALIAN CELL SURFACE RECEPTORS
Open Access
- Author:
- Boonyarattanakalin, Siwarutt
- Graduate Program:
- Chemistry
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 05, 2006
- Committee Members:
- Blake R Peterson, Committee Chair/Co-Chair
Scott Trent Feldman, Committee Member
Thomas E Mallouk, Committee Member
Avery August, Committee Member - Keywords:
- chemistry
synthetic organic
synthesis
organic
bioorganic
medicinal
chemical biology
biological chemistry
synthetic receptors
receptors
delivery
drug delivery
fluorescence
fluorescent
probes
cellular probes
cellular surface
protein uptake
synthetic receptor targeting
endocytosis
lipid rafts
fluorescent probes
his tag
receptor-mediated endocytosis
vancomycin
IgG
Fc
Pennsylvania Green
lipid bilayers
biomolecules
cholesterylamine
cholesterol
steroids
3ƒÒ-cholesterylamine
endosomes
lysosomes
listeria
mimicking
mimic
design and synthesis
antibody
antibodies - Abstract:
- Receptors on the surface of mammalian cells function as sensors and mediators of uptake of specific ligands in the extracellular environment. These biomolecules reside on the cellular plasma membrane, the protective lipid bilayer that envelops the cell to guard the fragile inner cellular machinery from potentially toxic or opportunistic extracellular materials. Only small hydrophobic compounds passively diffuse across this hydrophobic barrier to rapidly penetrate into cells. More hydrophilic macromolecules such as proteins and DNA generally require specific active transport mechanisms to access the cell interior. Cell surface receptors are components of this active transport machinery and deliver cargo such as nutrients and growth factors into cells via the uptake process of receptor-mediated endocytosis. Mammalian cell surface receptors comprise at least three basic components: a ligand recognition motif projecting from the cell surface, a linker region, and a membrane-binding element that anchors the receptor to the plasma membrane. Receptors on the surface of mammalian cells promote the uptake of cell-impermeable ligands by receptor-mediated endocytosis. To mimic this process, we synthesized small molecules designed to project ligand-binding motifs from the surface of living mammalian cells. These synthetic receptors comprise N-alkyl derivatives of 3ƒÒ-cholesterylamine as the plasma membrane anchor linked to binding motifs that target cell-impermeable macro and small molecules such as antidinitrophenyl IgG, proteins fused to oligohistidine, human IgG, and the antibiotic vancomycin. The cellular uptake of ligands mediated by 3ƒÒƒ{cholesterylamine derived synthetic receptors is proposed to mimic endocytic cellular penetration mechanisms employed by certain protein toxins and viruses. These mechanisms are highly complex at the molecular level and are thought to involve plasma membrane subdomains termed lipid rafts and/or endocytosis involving the protein clathrin. These nonnatural receptors mimic many natural receptors by avidly associating with cell surfaces (typical cellular t1/2 ~ 20 h), dynamically cycling between plasma membranes and intracellular endosomes (typical recycling t1/2 ~ 3 min), association with proposed lipid raft membrane microdomains, and delivery of cell-impermeable ligands to late endosomes/lysosomes. Synthetic cell surface receptors have potential applications as cellular probes, tools for drug delivery, and modulators of biological systems.