Andrew Pearson

Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors

Galectin‐3 is extensively involved in metabolic and disease processes, such as cancer metastasis, thus giving impetus for the design of specific inhibitors targeting this β‐galactose‐binding protein. Thiodigalactoside (TDG) presents a scaffold for construction of galectin inhibitors, and its inhibition of galectin‐1 has already demonstrated beneficial effects as an adjuvant with vaccine immunotherapy, thereby improving the survival outcome of tumour‐challenged mice. A novel approach—replacing galactose with its C2 epimer, talose—offers an alternative framework, as extensions at C2 permit exploitation of a galectin‐3‐specific binding groove, thereby facilitating the design of selective inhibitors. We report the synthesis of thioditaloside (TDT) and crystal structures of the galectin‐3 carbohydrate recognition domain in complexes with TDT and TDG. The different abilities of galactose and talose to anchor to the protein correlate with molecular dynamics studies, likely explaining the relative disaccharide binding affinities. The feasibility of a TDT scaffold to enable access to a particular galectin‐3 binding groove and the need for modifications to optimise such a scaffold for use in the design of potent and selective inhibitors are assessed.

Synthesis of simple heparanase substrates

Heparanase degrades heparan sulfate (HS) chains on proteoglycans; elevated levels of heparanase expression correlate with tumour cell metastatic potential and vascularity, and reduced post-operative survival of cancer patients. Consequently, heparanase expression is considered a biomarker for cancer detection. Although several heparanase assays have been developed, most require the preparation of heterogeneous, (radio)labelled HS substrates and rely on the separation of enzymatically-degraded products on the basis of molecular size. In studies directed towards the development of a more direct heparanase assay, a series of glucuronides and glycosyl glucuronides were synthesised as putative heparanase substrates. These compounds were designed with various aryl aglycones that could be measured spectrophotometrically upon hydrolysis of the glycosidic linkage by heparanase. It was found that the N-sulfated 4-nitrophenyl glycosyl glucuronide 24 and the N-sulfated methylumbelliferyl glycosyl glucuronide 26 were hydrolysed by recombinant human heparanase. These compounds represent the simplest substrates of heparanase reported to date.

Understanding the early transition needs of diverse commencing university students in a health faculty: informing effective intervention practices

The engagement and retention of commencing students is a longstanding issue in higher education, particularly with the implementation of the widening student participation agenda. The early weeks of the first semester are especially critical to student engagement and early attrition. This study investigated the perceived early transition needs of three cohorts of commencing students in their first three weeks of university study in a Health Faculty. A short survey was developed based on a systematic understanding of student transition and supplemented by open-ended qualitative data. The results showed a stable, consistent pattern of early transition needs across the cohorts, with commencing students expressing most concern about accessing resources, balancing work, family and study commitments, establishing peer relationships, and understanding the requirements and standards for early assessment tasks, particularly group tasks. Findings are discussed in terms of implications for early co-curricular and curricular interventions to enhance early student engagement and retention.

Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold†

Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH(1)) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.

A versatile synthetic approach toward diversity libraries using monosaccharide scaffolds

The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.

Synthesis of a novel pentasaccharide core component from the lipooligosaccharide of Moraxella catarrhalis

The novel pentasaccharide [p-(trifluoroacetamido)phenyl]ethyl 3-O-β-D-glucopyranosyl-4-O-β-D-glucopyranosyl-6-O-[2-O-(α-D-glucopyranosyl)-β-D-glucopyranosyl]-α-D-glucopyranoside (1), which includes a linker moiety to enable facile coupling to an antigenic protein, was synthesised as a component of a potential vaccine candidate against the Gram-negative bacterium Moraxella catarrhalis. This microorganism is one of three principal causative agents of otitis media in children. The pentasaccharide represents a common cross-serotype (A, B and C) structure from the lipooligosaccharides of Moraxella catarrhalis.

A peer observation program for the professional development of laboratory tutors

As undergraduate allied health programs continue to expand, there is increasing reliance on laboratory tutors, to engage, mentor and teach students. The bioscience laboratory is a specialised, tightly regulated learning environment and a potentially rich learning platform for students, but when the laboratory tutors are inadequately trained, the flow-on effects to the students can produce unfavourable learning outcomes. Traditionally, new tutors attend a generic sessional training workshop offered by the university. Due to the added health & safety considerations and the type of learning (kinaesthetic) that occurs in the laboratory, we identified a need for a specific professional development program for laboratory tutors. Our aim was to develop a program that allowed tutors to work within a framework tailored for laboratory teaching and, in a supportive environment, build teaching skills that promote student learning. Based on Lave’s theory of situated learning (Lave, 1991) and the recognised approach of supported reflective practice (Bell, 2001) we placed opportunities for peer observation at the centre of the program. The framework presented here (3P’s) was developed specifically for laboratory tutors and served as behavioural guidelines for peer observation sessions. Ten participants volunteered for the pilot program which concluded in 2015. Peer observation records and focus group data were gathered to evaluate the pilot program. Tutor feedback has initiated improvements in the program, and due to its overall success, it has been embedded into the recruitment/induction process for laboratory tutors in our department.