All projects in our group are focused around the chemical synthesis of architecturally interesting molecules which have biological and/or medicinal significance.  We are primarily involved in organic synthesis with an emphasis on peptides, carbohydrates and phosphorus-based transition-state analogs. Target molecules are often related to peptide/protein motifs which arise from post-translational modifications.

Our major area of research to-date has been the synthesis and incorporation of hydroxylated prolines into peptides.  Nature has relied heavily upon these post-translationally modified amino acids in two fascinating structural proteins. Mytilus edulis foot protein 1 (Mefp1) is one of a family of adhesive proteins, which stick molluscs to rocks in turbulent waters.

Figure 1.  The repeating decapeptide unit of Mefp1.

Collagens (the structural material of skin, nails and cartilage) consist of a domain in which every third amino acid is a glycine residue.  There is also a high incidence of proline and trans-4-hydroxyproline.

Figure 2.  Collagen triple helix and the Gly-Pro-Hyp triad.

The mechanical strength and three-dimensional architecture of these biomaterials underpins the survival of their host organism.  Through the synthesis of well-defined model peptides, and the careful study of their physical properties (using NMR, circular dichroism and other techniques) we are contributing to the understanding of how the structure of these molecules is related to their function.

In collaboration with Professor Stephen Kinrade (Lakehead University) we have been studying the complexation of 3,4-dihydroxyprolines with silicon (Fig. 3).  We believe that these amino acids, available by chemical synthesis in our laboratory, are important in the biomineralization of silica.  We are also working with Professor Nils Kröger (Georgia Tech) to confirm the occurrence of dihydroxyprolines in diatoms such as Thalassiosira pseudonana.

Figure 3.  Thallasiosira pseudonana (left) and the complexation of 2,3-trans-3,4-cis-DHP with silicon (right).

Histidinoalanine (HAL) is a bis-amino acid which constitutes a protein cross-link (i.e., where remote parts of a protein have reacted irreversibly to produce a covalent linkage).  Histidinoalanine has been identified in a range of environments:  phospho-proteins of bivalve molluscs, milk products which have been heat-treated and in human tissues (e.g., eye cataracts).  We have embarked upon the synthesis of the various regio- and stereoisomers of this compound.  The theonellamides are an interesting family of cyclic peptides which showcase the HAL motif.

Figure 4.Theonellamide F with the τ-HAL residue in red.

In some congeners of the theonellaimides, the HAL residue is glycosylated.  This is an important conceptual bridge to our ongoing interest in how carbohydrate motifs affect the conformation and behavior of peptides and proteins.  We have recently synthesized a glycosylhistidine and are working on new methods to link sugars and peptides.

Glycosides of trans-4-hydroxyproline have been known for a long time in plants.  More recent discoveries include the identification of a pentasaccharide attached to Pro¹⁴³ in SKP1, a protein associated with ubiquitination in the slime mould Dictyostelium, and some novel O-glycans in Art v 1, the major allergen of mugwort (Artemisia vulgaris).  The chemical and enzymatic synthesis of glycosides of Hyp is plagued by low yields. Retrosynthetically, there are two potential disconnections of the glycosidic bond (designated a and b, Figure 3. While approach a is conventional, it is only partially successful because the axial hydroxy group of trans-4-hydroxyproline is a poor nucleophile.  We are investigating an alternative approach, whereby we switch the roles of the sugar and the amino acid in O-glycoside formation (route b).

Figure 5.  Synthesis of β-glycosides.