| Project/Area Number |
20K15407
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2020-04-01 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
|
|---|
| Keywords | Biosynthesis / Enzymes / mRNA display / Bioengineering / Biochemistry / Natural products / Thiopeptides / Combinatorial synthesis |
|---|
| Outline of Research at the Start |
Thiopeptides are natural products possessing strong antibacterial activity, which can often overcome antibiotic resistance. Characterization of novel thiopeptides and their modes of action aids the development of the next generation antibiotics, and may directly provide potential drug candidates. Here we propose to identify and characterize new thiopeptides with the ultimate goal of devising a platform for combinatorial biosynthesis of natural product-like compounds. We believe that this research will allow us to utilize thiopeptides as molecular scaffolds for drug discovery purposes.
|
| Outline of Final Research Achievements |
The work focused around two major directions. 1. Development of an mRNA-display based platform for de novo discovery of pseudo-natural lactazole-like thiopeptides with novel bioactivities. We have established the proposed platform and showed its utility by discovering dozens of pseudo-natural products with designed biological activities. The development entailed reengineering of in vitro lactazole biosynthesis, development of library construction protocols, establishment of a general synthetic strategy for modular access to the discovered structures, and finally, biochemical characterization of the synthesized selection hits. 2. In vitro reconstitution of lactazole-like biosynthetic enzymes. We have successfully produced 12 enzymes from 4 biosynthetic gene clusters (BGCs) homologous to laz BGC. All expressed enzymes were active, and catalyzed reactions analogous to Laz enzymes, which simplified the analysis, but crucially, had a divergent substrate specificity profiles.
|
| Academic Significance and Societal Importance of the Research Achievements |
Discovery of new pharmaceuticals is a major challenge in the modern biomedical research. This research addresses the need for new methods to discover compounds with good biological activities and favourable pharmacological profiles using bacterial natural products as an inspiration.
|
