Area of Interest:
All projects in our group are focused around the chemical synthesis of architecturally interesting molecules that have biological and/or medicinal significance. Our group is engaged in mainstream, modern organic synthesis, with an emphasis on peptides and glycopeptides. Target molecules typically contain peptide/protein motifs that arise from post-translational modifications (PTMs) or non-ribosomal peptide synthesis (NRPS).
Our major area of research to-date has been the synthesis and incorporation of hydroxylated prolines into peptides. Using NMR, we have studied the effect of proline hydroxylation on peptide conformation. We have synthesized the repeating decapeptide (Fig. 1) of an adhesive protein produced by Mytilus edulis. In concert with a family of related proteins, Mefp1 mediates adhesion of mussels to rocks in turbulent waters.
Figure 1. The repeating decapeptide unit of Mefp1.
Virotoxins are cyclic heptapeptides that were isolated from Amanita virosa (Fig. 2) in the 1980s by Wieland and co-workers. These compounds have comparable toxicity to the notorious phalloidins; one bite of the Amanita phalloidesmushroom can kill an adult. We are engaged in a total synthesis of viroidin and seek to determine the role of the dihydroxyproline residue in assuring the bioactive conformation that binds to F-actin
Figure 2. Amanita virosa produces viroidin.
Our interest in hydroxyprolines has extended, in recent years, to glycosylated residues. Hydroxyproline glycosides have been well-known in plants for many years. To-date, no examples have been isolated from mammalian sources. Two glycopeptides targets are under study in our laboratory. Skp1 is a mediator of ubiquitination. In the slime moldDictyostelium, the protein is a target of proline hydroxylation and subsequent glycosylation (Fig. 3). These post-translational modifications are vital to the life cycle of the organism. Moreover, hydroxylation and glycosylation of Skp1 appear to be more general phenomena in lower eukaryotes, including Toxoplasma gondii, the causative agent of toxoplasmosis. We are working in collaboration with West (University of Oklahoma Health Sciences Center) to develop probes and inhibitors for key enzymes in the post-translational processing.
Figure 3. Proposed structure of glycoside region of Skp1.
β-Arabinosylated hydroxyprolines have been identified in the proline-rich domain of Art v 1, the major allergen of mugwort (Artemesa vulgaris). This epitope appears to be important in the allergic reaction. We are working to synthesize the β-L-Ara-Hyp motif to study, in collaboration with Altmann (BOKU, Vienna), the minimal requirement for recognition of the allergen.
Figure 4. Art v 1 from Artemesa vulgaris has a polyproline domain rich in β-L-Ara-Hyp residues.
Theonellamides are structurally novel bicyclic peptides, characterized by a bridging histidinoalanine (HAL) residue. Histidinoalanine has been isolated from a range of sources: phosphoproteins of bivalve mollusks, milk products that have been heat-treated and human tissues (e.g., eye cataracts). The theonellamides are the first example of HAL in a small, well-defined molecule. Theopalauamide, a glycosylated analog, has nanomolar antifungal activity and has been shown to disrupt fungal cell membranes by binding to ergosterol. We are working toward a total synthesis of theonellamide C (Fig. 5).
Figure 5. Theonellamide C.
Awards & Honors:
LSU College of Science Graduate Teaching Award (2013)
Easterfield Medal (2001) of the NZIC/RSC
Taylor, C. M.; Northfield, S. E.; Wang, C. K.; Craik, D. J., “Native peptide folding dominates over stereoelectronic effects of prolyl hydroxylation in loop 5 of the macrocyclic peptide kalata B1,” Tetrahedron 2014, 70, 7669-7674.
Xie, N.; Taylor, C. M., “Synthesis of oligomers of β-L-arabinofuranosides of (4R)-4-hydroxy-L-proline relevant to the mugwort pollen allergen, Art v 1,” J. Org. Chem. 2014, 79, 7459-7467.
Yadav, S.; Taylor, C. M., ““Synthesis of orthogonally protected (2S)-2-amino-adipic acid (α-AAA) and (2S,4R)-2-amino-4-hydroxyadipic acid (Ahad),” J. Org. Chem. 2013, 78, 5401-5409.
Taylor, C. M.; Karunaratne, C. V.; Xie, N., “Hydroxyproline glycosides: some recent, unusual discoveries,” Glycobiology 2012, 22, 757-767.
Van der Wel, H.; Johnson, J.M.; Xu, Y.; Karunaratne, C.V.; Wilson, K.D.; Vohra, Y.; Boons, G.-J.; Taylor, C.M.; Bendiak, B.; West, C.M., “Requirements for Skp1 processing by cytosolic prolyl-4(trans)-hydroxylase and α-N-acetylglucosaminyltransferase enzymes involved in O2-signaling in Dictyostelium,” Biochemistry 2011, 50, 1700-1713.
Xie, N.; Taylor, C. M., “Synthesis of a dimer of β-(1,4)-L-arabinosyl-(2S,4R)-4-hydroxyproline inspired by Art v 1, the major allergen of mugwort,” Org. Lett. 2010, 12, 4968-4971.
Edagwa, B. J.; Taylor, C. M., “Peptides containing γ,δ-dihydroxyleucine,” J. Org. Chem. 2009, 74, 4132-4136.
Wong, D.; Taylor, C. M., “Asymmetric synthesis of erythro-β-hydroxy-L-asparagine,” Tetrahedron Lett. 2009, 50, 1273-1275.
Taylor, C.M.; Wang, W., “Histidinoalanine: a crosslinking amino acid,” Tetrahedron, 2007, 63, 9033-9047.