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Generation of novel rapamycin structures by microbial manipulations
H Nishida1, T Sakakibara, F Aoki
1Central Research Division, Pfizer Pharmaceuticals Inc., Aichi, Japan.
The Journal of Antibiotics
|July 1, 1995
Summary
Researchers discovered a new rapamycin-producing bacterium, Actinoplanes sp. N902-109. This led to the creation of novel rapamycin analogs with modified structures, showing significant immunosuppressive activity.
Area of Science:
- Microbiology
- Biochemistry
- Immunology
Background:
- Rapamycin is a crucial immunosuppressive drug.
- Developing novel rapamycin analogs can improve therapeutic potential.
- Microbial fermentation is a key source for natural products.
Purpose of the Study:
- To isolate and characterize a new rapamycin-producing microorganism.
- To generate novel rapamycin analogs through biotransformation.
- To evaluate the immunosuppressive activity of the newly synthesized analogs.
Main Methods:
- Isolation and identification of a novel Actinoplanes sp. strain (N902-109).
- Utilizing cytochrome P-450 inhibition and precursor feeding for targeted modifications.
- Employing biotransformation techniques to create rapamycin analogs.
- Assessing immunosuppressive properties using the mixed lymphocyte reaction assay.
Main Results:
- A new rapamycin-producing culture, Actinoplanes sp. N902-109, was successfully isolated.
- Novel rapamycin analogs with modifications at multiple sites (C-4, C-9, C-16, C-27, C-28, C-39) were synthesized.
- The generated analogs demonstrated significant immunosuppressive activity in vitro.
Conclusions:
- Actinoplanes sp. N902-109 is a valuable source for rapamycin production and analog synthesis.
- Biotransformation strategies enable the creation of diverse rapamycin derivatives.
- The novel analogs hold potential for future immunosuppressive therapies.