1. Novel molecular mechanism of communication (sensing) between mammalian cells and Gram-positive bacteria – new pathway and drug targets to combat super-bacteria (superbug).
- Microbiology and Biochemistry – Discovered and characterized the dimerization of sortase A, an enzyme that catalyzes the display of the virulence factors on the surface of Gram-positive bacteria.
- Enzymology – Classic enzyme kinetics study (Km, kcat, and kcat/Km) showed the sortase A dimer is inactive when the sortase A monomer is the active form in vitro.
- Protein engineering – Created monomer-only sortase A mutant.
- Genetic and Cellular Engineering – Using a gene-splicing technology, knocked out wild-type sortase A gene from S. aureus genome (KOA), then knocked in monomeric sortase A mutant gene back to create a “always-on” S. aureus cell strain.
- Bacteriology and tissue culturing – Established a quantitative bacterial invasion assay and measured the infectious efficacy of bacterial cells.
- X-ray crystallography – Purified the sortase A dimer in large quantity. Obtained X-ray crystal structure of sortase A dimer at 2.0Å resolution.
- Conclusion: Equilibrium of sortase A dimerization on Gram-positive bacterial surface regulates the bacterial infection towards the mammalian cells.
2. BIOAI – Marginal artificial intelligence platforms for biomedical applications
We believe that artificial intelligence should never design nor decide for humans. In BIOAI research, human intellect should always come first and guide the artificial intelligence to aid the further design and decision-making process with precision and efficiency.
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- Anti-infective Drug Discovery
- Small molecule anti-infective drug design
- Cell-based high-throughput screening (HTS) – Screened >20,000 small molecule libaray and afforded 5 lead compounds that can antagonize S. aureus infection ex vivo.
- Biophysics - Characterized the inhibition between the small molecules and sortase A (Gen 1).
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- (In Progress) Deep Learning (DL) and Reinforcement Learning (RL) - 3D-QSAR fragment-based drug leads (Gen 1) optimization and design.
- In Progress) Medicinal Chemistry – Synthesize the designed molecules and ex vivo validation (Gen 2).
- (In Progress) Animal studies – Pharmacology and Toxicity studies for the drug candidates.
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- Immuno-anti-bacterial infection
- Functional proteomics studies between sortase A and mammalian proteins.
- Directed Deep Learning (DDL) - Identified 4 protein and peptide candidates.
- Immunology – Confirmed one pathway (defender) that can inhibit.
- Immuno-anti-bacterial infection therapy – Antibodies developed blocking the “traitor” molecule can reduce S. aureus infection.
- Immuno-anti-bacterial infection
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- (In Progress) Fuzzy Deep Learning (FDL) – Target-specific antibody optimization in the context of the human physiology.
- (In Progress) Animal studies – Pharmacology and Toxicity studies for the drug candidates.
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