Immunosuppressant Analogs Through Targeted Genetics

Cyclosporin brought the field of transplantation science into the mainstream of medicine. Unfortunately, long-term survival and quality of life for transplant recipients are still severely diminished. Recently, the natural products, FK-506 and rapamycin, have proven in studies to be safe, more potent, and more effective than cyclosporin. Furthermore, these drugs appear to act synergistically possibly because they interfere with different pathways of the immune response. Novel chemically-synthesized analogs of FK-506 and rapamycin have helped elucidate the mechanism of action of these drugs. Other new analogs could lead to less toxic drugs or new choices for combination therapy. We will develop genetic technology as an alternative to chemical synthesis for producing novel analogs. In Phase I, a genetic system would be developed in the producing micro-organism. In Phase II, the genetic tools would be used to manipulate the biosynthetic pathway by targeted gene inactivation or replacement. Analogs with tailored structural modifications could be produced inexpensively through fermentation. Novel structures would be patented, biologically tested, and open to licensing for clinical testing or further chemical development by interested partners.