The aim of our research group is to engineer biomimetic molecules using organic synthesis as a tool and amino acids as building blocks. We wish to utilize the functional group diversity of amino acids and the hydrogen bonding capability of peptides to develop interesting 3-dimensional supramolecular structures. In particular, we are interested in mimicking the activity of natural pore forming proteins or ion channels that are found in the cell membranes. Ion channels have two highly interesting properties: ion selectivity and the reversible opening-closing or gating. These properties of ion channels have been used for therapeutics as well as the development of molecular switches.
We are working on three focus areas:
- Peptide Synthesis – Development of improved methods of peptide synthesis.
- Self-Assembly – Development of functionalized pores as ion channel mimics.
- Functionalized Pores – Designing pores that can selectively transport ions or be gated.
Focus Area 1: Peptide Synthesis
Solid phase peptide synthesis has been an attractive method for synthesizing peptides as it is quick and the peptide synthesis can be automated. The heterogeneous reaction medium in solid phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable supports is an attractive alternative to solid phase peptide synthesis. Soluble polymer supports reported in the literature either have low loading capacities (i.e. number of attachment sites per gram of polymer) or have moderate solubility. We are interested in developing more efficient supports for peptide synthesis. We have developed poly(norbornene) supports that could be used to synthesize tri-octapeptides in 28-97% yields and natural products such as Leu-enkephalin and Segetalin A. The supports could be used multiple times for peptide synthesis without any decrease in yields. The poly(styrene) supports have been used to synthesize tri-hexapeptides in 59-85% yields.
Focus Area 2: Self-assembly
The selectivity of ion channel proteins has been attributed to the presence of functional groups inside the pore. There are very few examples in the literature of internally functionalized pores for biomimetic signal transduction. Therefore, we wish to develop pores that can be easily made and can be functionalized in the interior. To meet this dual objective, we have designed two novel approaches to develop functionalized pores –
- Using peptides as templates to form polymer pores.
- Incorporating aromatic units that can be potentially used as sites for internal functionalization into pore forming peptide scaffolds.
Focus Area 3: Functionalized Pores
Our goal is to develop ion selective or gated synthetic ion channels. Ion selective ion channels can be potentially useful therapeutic agents. Therefore, we wish to develop small peptides that can selectively transport ions across the bilayer. The development of gated ion channels was motivated by the fact that such channels have potential applications as molecular switches or sensors.We have developed octapeptides from alanine and aromatic units such as aminobenzoic acid that form cation selective pores. We believe that at least one aromatic unit is proximal to the pore. We are currently utilizing the aromatic units to tune the selectivity and activity of these pores. We are also modifying the aromatic units to obtain stimuli responsive pores.