Transpeptidase (TP) and transglycosylase (TG) on the bacterial cell surface are essential for cell wall synthesis, and many antibiotics have been developed to target the transpeptidase; however, the problem of antibiotic resistance has inevitably arisen and caused a major threat in treating bacterial infection. The transglycosylase has been considered to be another excellent target, but no antibiotics have been developed to target this enzyme.

We have successfully obtained functional full-length transglycosylases to develop a high-throughput screening assay for finding new hit compounds that can replace the known inhibitor moenomycin binding with TG (2008). Subsequently, we determined the crystal structure of E. coli full-length membrane-bound bifunctional pencillin-binding protein PBP1b in complex with the antibiotic moenomycin (2009). We have also solved the crystal structure of S. aureus membrane-bound monoglycosyltransferase in complex with a substrate lipid II analog (2012), which for the first time revealed the lipid-II-bound acceptor site of TG. The mechanistic characterization of the lipid II dimerization into lipid IV in the peptidoglycan synthesis was therefore clarified at the atomic level.The three-dimensional interaction network between moenomycin/lipid II and TG domain provides a foundation for structure-based drug design. Over the years there are mainly three classes of inhibitors, including substrate lipid II analogs, moenomycin (lipid IV) analogs, and novel inhibitors identified through screening methods with unknown binding sites. We also focused our efforts on the protein complex structure with novel inhibitors which revealed unexpected binding sites on TG, providing valuable information to guide antibiotic optimization for improved inhibitory potency (2019).

The figure above is a summary of potential inhibitors targeting the bacterial transglycosylase (GT51 domain). The lipid-II-analog-bound S. aureus MgtA structure (PDB 3vmt) with an additional moenomycin A modeled in the donor site (PDB 6ftb and 3hzs) was shown in the middle. Shown in the surroundings are selected moenomycin and lipid II analogs on the top and novel non-saccharide inhibitors at the bottom, with compound name and references labeled for each.




Influenza viruses continue to cause annual epidemics and pose the threat of a deadly global pandemic. Vaccination is the most effective method to control and prevent the morbidity and mortality resulting from influenza virus infections in humans. However, influenza virus is constantly changing and the current flu vaccines are only effective against closely matched circulating strains. As a consequence, flu vaccine needs to be reformulated every year. Over the years we have pioneered an improved flu vaccine design using the monoglycosylated form of the major surface glycoprotein hemagglutinins (HAs). Understanding how glycans on HAs affect the immune response and knowledge of how broadly neutralizing antibodies are induced will pave the way for a cross-protective influenza vaccine that does not require frequent updates or annual immunizations. Trimming down the structurally non-essential glycans on HA may be the key for a better flu vaccine.

Recombinant monoglycosylated hemagglutinin (HAmg) with an intact protein structure from either seasonal or pandemic H1N1 can be used as a vaccine for cross-strain protection against various H1N1 viruses in circulation from 1933 to 2009 in mice and ferrets. In the HAmg vaccine, highly conserved sequences that were originally covered by glycans in the fully glycosylated HA (HAfg) are exposed and thus, are better engulfed by dendritic cells (DCs), stimulated better DC maturation, and induced more CD8+ memory T cells and IgG-secreting plasma cells. Single B-cell RT-PCR followed by sequence analysis revealed that the HAmg vaccine activated more diverse B-cell repertoires than the HAfg vaccine and produced antibodies with cross-strain binding ability (2014). The HAmg vaccine elicits cross-strain immune responses that may not only mitigate the current need for yearly reformulation of strain-specific inactivated vaccines, but also map a new direction for universal vaccine design. We further provided a simple and practical procedure to develop monoglycosylated influenza vaccine using the current egg-based process (2019).




Pancreatic cancer has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. After finding that overexpression of Interleukin-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients (2013), we identified a newly derived monoclonal antibody (D9) against IL-17RB which blocked tumor metastasis and promoted survival in a mouse xenograft model (2015). We further determined the complex structure of IL-17RB bound by Fab of D9, which revealed an important loop region, clearly defined as the epitope for D9, in an unusual conformation (2019). This conformation presumably disrupts the interaction between ligand IL-17B and receptor IL-17RB, and prevents the receptor dimerization that is required for activation of the IL-17B/IL-17RB signaling. Humanization and affinity maturationof D9 are ongoing for potential therapeutic applications.

In addition to cancer-specific interleukin receptors, the change in glycosylation pattern can also be a distinct feature of cancer cells. Globo-series glycolipids, in particular the stage-specific embryonic antigen (SSEA4), have been found to be highly expressed on the surface of almost all cancer cells, including brain, lung, breast, esophagus, stomach, liver, bile duct, pancreas, colon, kidney, cervix, ovary and prostate. We have recently determined the crystal structures of a mouse IgG3 monoclonal antibody MC813 in complex with SSEA4, as well as a human IgG1 monoclonal antibody isolated from a cancer patient (unpublished), also in complex with SSEA4 (2019).  MC813 can suppress SSEA4+ brain tumor growth in vivo possibly through both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). The structural features and the different binding modes provide basis for understanding the anti-cancer effects carried out by these antibodies.


GRC, Taiwan Academy of Sciences

128 Academia Road Section 2

Nankang District

Taipei 11529, TAIWAN​​

Tel: 886-2-27898072


Designed by Cayra Chen