•  cma@as.edu.tw
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RESEARCH INTERESTS

Structure and functions of membrane glycoproteins in drug discovery

1. In order to overcome the problems of drug-resistant bacterial infection, the membrane-bound bifunctional transglycosylase, has been chosen for structural and functional analysis. We have determined the X-ray crystal structures of this membrane-bound enzyme in complex with its inhibitor moenomycin, and with its substrate lipid II analog, leading to the proposed mechanism of peptidoglycan synthesis. In addition, the crystal structure of a membrane protein complex, the key component of divisome ftsBLQ has been determined to decipher the cell division process.
   1. Targeting the bacterial transglycosylase: antibiotic development from a structural perspective, X Chen, CH Wong, C Ma*. ACS Infectious Diseases, 5, 1493 (2019). (Times cited: 16)
   2. Structure of the heterotrimeric membrane protein complex FtsB-FtsL-FtsQ of the bacterial divisome. HTV Nguyen, X Chen, C Parada, AC Luo, O Shih, US Jeng, CY Huang, YL Shih* and C Ma*. Nat Commun. 14(1):1903 (2023).
2. We have discovered a simple and practical approach using traditional egg-based method to prepare a broad-spectrum split influenza virus vaccine that when vaccinated can induce cross-strain protection in mice.
   1. Egg-based influenza split virus vaccine with monoglycosylation induces cross-strain protection against influenza virus infections, YC Tseng, CY Wu, ML Liu, TH Chen, WL Chiang, YH Yu, JT Jan, KI Lin, CH Wong*, C Ma*. Proc Natl Acad Sci U S A, 116, 4200 (2019). (Times cited: 28)
   2. Better influenza vaccines: an industry perspective. JR Chen, YM Liu, YC Tseng, C Ma*. J Biomed. Sci., 27, 33 (2020). (Times cited: 66)
   3. Chimeric hemagglutinin vaccine elicits broadly protective CD4 and CD8 T cell responses against multiple influenza strains and subtypes. HY Liao, SC Wang, YA Ko, KI Lin, C Ma, TJR Cheng, CH Wong. Proc Natl Acad Sci U S A, 117, 17757 (2020). (Times cited: 18)
3. We isolated a plant lectin FRIL from the edible Lablab beans with superior anti-influenza and anti-SARS-CoV-2 activities. FRIL binds preferentially to complex-type N-glycans and neutralizes viruses that possess complex-type N-glycans on their envelopes. As a homotetramer, FRIL is capable of aggregating influenza particles through multivalent binding and trapping influenza virions in cytoplasmic late endosomes, preventing their nuclear entry. Remarkably, FRIL also effectively neutralizes SARS-CoV-2, preventing viral protein production and cytopathic effect in host cells. These findings suggest a potential application of FRIL for the prevention and/or treatment of influenza and COVID-19.
   1. A carbohydrate-binding protein from the edible Lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2. YM Liu, M. Shahed-Al-Mahmud, X Chen, TH Chen, KS Liao, JM Lo, YM Wu, MC Ho, CY Wu, CH Wong, JT Jan, C Ma*. Cell Reports, 32, 108016 (2020), selected as journal cover. (Times cited: 62)
4. We have studied the effect of glycosylation on SARS-CoV-2 virus major surface Spike protein with regards to its role in ACE2 receptor binding and immune response, and developed a simple strategy for broad-spectrum COVID-19 vaccine design. The resulting mono-GlcNAc-decorated Spike vaccination can elicit superior B cell, Tfh cell and CD8 T cell responses, and protect hACE2 transgenic mice against infections of SARS-CoV-2 and the variants of concerns, such as the original Wuhan, Alpha, Beta, Gamma, Delta and more recently Omicron and its subvariants. Antibody responses from a structural perspective are also been studied with samples from COVID-19 vaccination and convalescent individuals. Several structures have been determined to understand the structural basis of anti-RBD neutralizing antibodies.
   1. Vaccination with SARS-CoV-2 spike protein lacking glycan shields elicits enhanced protective responses in animal models. HY Huang, HY Liao, X Chen, SW Wang, CW Cheng, M Shahed-Al-Mahmud, YM Liu, A Mohapatra, TH Chen, JM Lo, YM Wu, HH Ma, YH Chang, HY Tsai, YC Chou, YP Hsueh, CY Tsai, PY Huang, SY Chang, TL Chao, HC Kao, YM Tsai, YH Chen, CY Wu, JT Jan, TJR Cheng, KI Lin*, C Ma* and CH Wong*. Science Translational Medicine, 14, eabm0899 (2022), selected as online feature article. (Times cited: 33)
   2. Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine. CY Wu, CW Cheng, CC Kung, KS Liao, JT Jan, C Ma and CH Wong*. Proc Natl Acad Sci U S A, 119, e2019995119 (2022). (Times cited: 13)
   3. Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. KYA Huang, D Zhou, TK Tan, C Chen, HME Duyvesteyn, Y Zhao, HM Ginn, L Qin, P Rijal, L Schimanski, R Donat, A Harding, J Gilbert-Jaramillo, W James, JA Tree, K Buttigieg, M Carroll, S Charlton, CE Lien, MY Lin, CP Chen, SH Cheng, X Chen, TY Lin, EE Fry, J Ren, C Ma, AR Townsend, DI Stuart. Theranostics, 12, 1 (2022). (Times cited: 5)
   4. Breadth and function of antibody response to acute SARS-CoV-2 infection in humans. KYA Huang, TK Tan, TH Chen, CG Huang, R Harvey, S Hussain, CP Chen, A Harding, J Gilbert-Jaramillo, X Liu, M Knight, L Schimanski, SR Shih, YC Lin, CY Cheng, SH Cheng, YC Huang, TY Lin, JT Jan, C Ma, W James, RS Daniels, Rodney JW McCauley, P Rijal, Pramila, AR Townsend. PLOS Pathogens, 17, e1009352 (2021). (Times cited: 55)
   5. Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2. KA Huang*, X Chen, A Mohapatra, HTV Nguyen, L Schimanski, TK Tan, P Rijal, SK Vester, RA Hills, M Howarth, JR Keeffe, AA Cohen, LM Kakutani, YM Wu, M Shahed-Al-Mahmud, YC Chou, PJ Bjorkman, AR Townsend, C Ma*. Nat Commun. 14(1):311 (2023).
5. We have generated a monoclonal antibody to target an important membrane receptor IL-17RB for pancreatic cancer, which has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. We found that overexpression of IL-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients.
   1. Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines, HH Wu, WW Hwang-Verslues, WH Lee, CK Huang, PC Wei, CL Chen, JY Shew, EY Lee, YM Jeng, YW Tien, C Ma, WH Lee*, J Exp Medicine, 212, 333-349 (2015).
   2. Structural basis of interleukin-17B receptor in complex with a neutralizing antibody for guiding humanization and affinity maturation. WH Lee, X Chen, IJ Liu, JH Lee, CM Hu, HC Wu, SK Wang, WH Lee* and C Ma*. Cell Reports 41(4):111555 (2022).
6. In August 2022, the technologies related to COVID-19 vaccine and antibodies have been transferred to a new startup biotech company by Academia Sinica for developing products such as broad-spectrum vaccines and antibodies with glycoengineering technologies.