Projects

Research Institute of Biopharmaceutical Sciences

Bioinformatics

Principle investigator: Dr Jia Meng

Bioinformatics is the melding of molecular biology with computer science. The need for bioinformatics capabilities has been precipitated by the explosion of biological data resulting from the Human Genome Project, the Cancer Genome Atlas and other high-throughput profiling efforts underway in laboratories around the world. As the key to extracting biologically meaningful information from these massive datasets, bioinformatics is essential for an in-depth understanding of human diseases as well as for the identification of new molecular targets and therapeutic molecules for drug discovery.

G protein-coupled receptors (GPCRs)

Principle investigator: Zhiliang Lu

We endeavour to identify the structural determinants of peptide analogues and their cognate GPCRs involved in LiSS which will assist in the development of signal-selective ligands/drugs, directed at different clinical endpoints with improved therapeutic outcomes and reduced side-effects.

When activated, GPCRs can also interact with different G proteins or other GPCR-interacting proteins (GIPs) at the intracellular side to mediate different pharmacological actions. We have shown that binding of different peptides to the same receptor can stabilise different receptor shapes that preferentially activate different pharmacological actions which we termed “ligand-induced selective signalling”.

G protein-coupled receptors (GPCRs) constitute the largest superfamily of cell surface signalling proteins which are characterised by the architecture of 7-transmembrane domains. GPCRs play a pivotal role in mediating signal transduction of endogenous ligands, such as neurotransmitters and hormones, from the extracellular side into the intracellular side of the cells resulting in changes of cellular physiological functions. Dysfunction of GPCRs is closely linked with multiple diseases, including aging and cancer development and metastasis.

About 40 percent of current clinical drugs exert their pharmacological effects via GPCRs, but they only target a few GPCRs so far. Therefore, huge efforts are currently underway to develop new GPCR-based drugs for treatment of different diseases.

Our research focuses mainly on elucidation of how neuropeptides bind to their cognate GPCRs at the extracellular side of the cell surface and understanding how the peptide binding induces receptor protein shape changes that mediate different pharmacological actions. The figure below shows how a GnRH peptide binds to its receptor, which assists in structure-based drug design. Both GnRH peptide agonists and antagonists have been extensively used for the treatments of hormone-dependent diseases such as endometriosis, prostate and breast cancers, and assisted reproductive technologies. This is reflected by the annual USD 2.6 billion sales of GnRH analogues as interventive drugs.

We endeavour to identify the structural determinants of peptide analogues and their cognate GPCRs involved in LiSS which will assist in the development of signal-selective ligands/drugs, directed at different clinical endpoints with improved therapeutic outcomes and reduced side-effects.

Targeting the mycobacterial cell envelope with biopharmaceuticals

Principle investigator: Dr Boris Tefsen

Each year, more than eight million people get infected with mycobacterium tuberculosis and over a million patients die from tuberculosis (WHO, Global tuberculosis report. 2014). Clearly, this pathogen is still a major threat to public health around the world and particularly in developing countries like India and China. Moreover, the growing number of infections caused by multidrug-resistant strains is alarming and calls for new approaches to combat M. tuberculosis. The cell envelope of this bacterium is essential for survival inside the human host and is composed of many different complex molecules like polysaccharides, peptidoglycan and mycolic acids (Jackson, M., M.R. McNeil, and P.J. Brennan, Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis. Future Microbiol, 2013. 8(7): p. 855-75).

Biopharmaceuticals that target and subsequently degrade these molecules or inactivate the enzymes that synthesise them could be ideal therapeutics. Such biologics can be produced in several (humanised) non-mammalian culture systems. Moreover, Traditional Chinese Medicine is a rich source of many interesting biopharmaceuticals. Regardless their origin, these compounds can be tested in the in vitro model systems that are currently running in our laboratory, which has its focus on better understanding the biosynthesis of the mycobacterial cell envelope.

Prevention of advanced and metastatic cancers

Principle investigator: Dr Meng Huee Lee

One of the major challenges in the treatment of advanced cancers is the capability of the tumour cells to proliferate to other parts of the body (usually through the bloodstream) and form secondary tumours in a process called “metastasis”. Unlike normal cells, cancer cells have the unique ability to break down the extracellular matrix (ECM) that restricts cell movement through the production of a group of highly special protein-degrading Matrix Metalloproteinase (MMP) enzymes.

The aim of our research group is to find ways to prevent cancer metastasis by the inhibition of these MMP enzymes. To this end, we redesign the natural inhibitors of MMP enzymes (a group of proteins named “TIMPs”, Tissue Inhibitors of Metalloproteinases, that exist naturally in the body) by means of genetic and protein engineering in order to increase their efficiency against the MMP enzymes.

T-cells

Principle investigator: Dr Hebin Liu

T-cells are essential components of the immune system that scan other cells in the body for signs of disease, such as cancer and infection. They interact with abnormal cells via a molecule on their cell surface known as a T-cell receptor (TCR).

The 'SH2 domain containing leukocyte phosphoprotein of 76 kDa' (SLP-76) is a key immune cell adaptor protein that influences numerous signalling cascades following activation of the TCR. SLP-76 controls the onset and severity of immune-related diseases such as arthritis, and regulates of the release of the AIDS virus (HIV-1) and its cell-to-cell transmission in T-cells. Thus, SLP-76 is an important and novel target for immunotherapy for immunological and viral diseases.