A membrane-spanning macrocyclic bolaamphiphile lipid mimic of archaeal lipids

Abstract

The synthesis of a 72-membered macrocyclic tetraester bolaamphiphile is accomplished in six chemical steps from commercially available starting materials using copper-accelerated azide–alkyne coupling to close the macrocycle in high yield. Related diester amphiphiles and an acyclic tetraester bolaamphiphile were also prepared. The set of lipids bearing nitrophenyl phosphate head groups were incorporated into phospholipid vesicles but failed to undergo phosphate hydrolysis in basic conditions, undergoing efficient elimination in competition. The same lipid cores bearing phosphate-linked nitrobenzoxadiazole (NBD) head groups also incorporated into phospholipid vesicles and the NBD fluorescence was quenched with cobalt ions. The proportion of membrane-spanning bolaamphiphiles was determined from the ratio of cobalt quenching in the presence and in the absence of a detergent. The macrocyclic bolaamphiphile is incorporated into phospholipid vesicles such that 48 ± 4% of the NBD head groups are in the outer leaflet, consistent with a membrane-spanning orientation. The acyclic bolaamphiphile is incorporated with 75 ± 3% of the NBD head groups accessible to quencher in the absence of a detergent suggesting U-shaped incorporation in the outer leaflet of the bilayer membrane. In ring size and spanning ability, the macrocyclic bolaamphiphile mimics naturally occurring macrocyclic archaeal lipids.

A Self‐Assembling Tripeptide‐Based Fluorescence Bio‐Nanosensor

“…Besides the thermodynamic rules, in combination with the high selectivity of copper ion sensing, the nanorod morphology drives us to hypothesize that a cation‐π interaction could involve in the assembling process of YFF NPs. Because the copper ions are not only the strong quencher for the fluorescence, [17,18] but also the strongest binding counterion to the benzene rings [19] . More importantly, it is worth noting that the π‐π interactions is orientation‐dependent, [20–22] which can account for the oriented assembly of YFF NPs.…”

Water Permeability and Elastic Properties of an Archaea Inspired Lipid Synthesized by Click Chemistry

“…15 Notably, the [3+2] azide-terminal alkyne cycloaddition approach has been used for lipid functionalization 16 and tetra-acyl phospholipid synthesis. 17 However, in this work we demonstrate the first example of the synthesis of phytanyl side chain incorporated tetraether lipids with 1,4-triazole rings. We next confirm the ability of lipids incorporating 1,4-triazole rings to form stable small and giant vesicles and examined their physical and mechanical properties using a micropipette aspiration technique.…”

“…To access structural diversity in the hydrophobic moiety of the lipids and to tune membrane properties, we used Huisgen 1,3-dipolar cycloaddition strategy (click chemistry) to design and synthesize a tetraether lipid incorporating phytanyl side chains and polar 1,4 triazole rings known to change lipid packing (Figure ). Notably, the [3+2] azide-terminal alkyne cycloaddition approach has been used for lipid functionalization and tetra-acyl phospholipid synthesis . However, in this work we demonstrate the first example of the synthesis of phytanyl side chain incorporated tetraether lipids with 1,4-triazole rings.…”

HA-Modified R8-Based Bola-Amphiphile Nanocomplexes for Effective Improvement of siRNA Delivery Efficiency

“…On the other hand, previously developed bola-amphiphiles often contain longer hydrophobic chains, making them more likely to form a U-shaped conformation. This conformation was likely to cause greater cytotoxicity to cells, thereby reducing the biocompatibility …”

“…This conformation was likely to cause greater cytotoxicity to cells, thereby reducing the biocompatibility. 10 Cell penetrating peptides (CPPs) are short peptides consisting of 5−30 amino acids and rich in lysine and arginine, which have been confirmed to improve the entry of biological macromolecules into cells. 11−13 Octa-arginine (R8) is a positively charged hydrophilic transmembrane peptide composed of eight arginines, which is commonly used to modify the nanocarriers for enhanced cellular uptake.…”