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Research

Research in our laboratory involves the creation of bioinspired, biomimetic, and biocompatible structures based on the combination of design, synthesis, characterization, and functional studies. The major areas of research include: protein-like folding molecules (foldamers); cavity-containing macrocycles; molecular and self-assembling nanotubes; ion and molecular channels; intramolecular delivery of ions and molecules; information-storing molecules, and the interaction of these structures, as functional molecular and supramolecular devices, with biological targets.

Folding structures (porous foldamers)

Mimicking protein folding with synthetically accessible structures

Since reporting on aromatic oligoamides adopting stable helical conformations, one of the earliest classes of folding oligomers, or foldamers, our group has been engaged in creating stably folded structures by controlling the conformational freedom of molecular strands having aromatic oligoamides, oligoureas, and other hybrid backbones. These synthetically accessible foldamers offer readily modifiable outer surfaces and hydrophilic inner pores of adjustable diameters and lengths, structural features that are typically seen with higher-order, i.e., tertiary and quaternary structures, of proteins. With their nanometer and sub-nanometer sized inner pores, our porous foldamers provide unique structural platforms for mimicking biomacrommolecules, especially proteins, resulting in the development of novel hosts, receptors, and channels that bind or transport a wide variety of molecules and ions.

Pore-containing macrocyclic structures

Creating non-deformable pores with cyclic structures

As part of our long-term interest in constructing and studying well defined pore-containing structures, several classes of donut-like cyclic structures, i.e., rigid macrocycles, have been discovered or rationally designed. The majority of our macrocycles share the same conformationally restricted backbones with the non-cyclic foldamers we created. These macrocycles, most are generated in highly efficient one-step reactions, are featured by their persistent shapes and non-deformable inner cavities with sub-nanometer to nanometer diameters. With their inner cavities of defined shapes and sizes, our macrocycles have served as host molecules for the binding and recognition of biologically important polar molecules and large cations. More recently, we developed another of macrocycles that offer inner cavities with multiple hydrogen-bond donors. With few precedents, such macrocycles bind anions with extraordinary affinities, which are finding applications in treating diseases such as cystic fibrosis and removing anion pollutants from environments.

Ion and molecular channels

Biomimetic cation, anion, and molecular channels including water channels for the translocation of ions and molecules across cell membranes

A major driving force for our development of pore-containing structures involves the mimicking of natural ion and molecular transport systems. Many of the donut-like macrocyclic molecules we created have a strong tendency for stacking into tubular structures that contain cylindrical inner pores. Based on such tubular stacks, we have constructed synthetic channels for transporting ions and water molecules across cell membranes. Our helical foldamers, with their hydrophilic inner pores, are able to facilitate the translocation of ions, water, various sugars and sugar alcohols across cell membranes. As molecular and supramolecular channels that mimic the functions of biological (protein) channels, our macrocycles and foldamers offer synthetically accessible and tunable structures based on which invaluable insights into biological transport phenomena are gained. Such artificial channels are being developed into membrane-bound antibiotics, anticancer reagents, and molecular or supramolecular devices for drug delivery.

Intracellular delivery of ions and molecules

Facilitating cellular uptake of membrane-impermeable ions and molecules for the manipulation cellular activities and related biomedical applications

In line with our interests in developing pore-forming structures that span cell membranes, strategies for facilitating the uptake of membrane-impermeable, bioactive ions and molecules into cells are being developed. One approach involves the intracellular delivery of ions and molecules through the pores of our folding and macrocyclic molecules. Ions such as the calcium and chloride ions that play important biological roles are introduced into cells followed by monitoring the corresponding change in cellular behavior. Membrane impermeable molecules that either protect or destroy cells are also introduced as preservative or therapeutic reagents. We are also developing strategies for modifying otherwise membrane-impermeable, bioactive molecules into derivatives that are membrane-permeable, which, upon intracellular uptake, are converted into their original bioactive forms.

Information-storing double-stranded molecules

Specifying intermolecular association with hydrogen-bonded duplexes with DNA-like sequence-specificity

We have designed information-carrying molecules based hydrogen-bonded molecular duplexes with sequence-specific programmability and tunable stability. These double-stranded molecules, featured by their DNA-like programmable specificity and high stability, have resulted in precisely controlled intermolecular interactions, and have served as “molecular glues”, i.e., programmable association units for directing the assembly and/or reactions of various structural units that have been used in diverse fields. Examples include the nucleation and stabilization of beta-sheets, the design of supramolecular block copolymers, and the templation of organic reactions.