Research Project
2005846
There is an increasing need for novel broad-spectrum antifungal agents to combat systematic mycoses in immunocomprised patients, particularly as resistance emerges to current therapies. The natural product rapamycin has potent fungicidal activity and is orally bioavailable, but clinical exploitation of this is precluded by the compound's immunosuppressive effects in human. Both activities are apparently due to the simultaneous interaction of rapamycin with the intracellular proteins FKBP and TOR/FRAP in fungal cells or human T cells, blocking signal transduction by TOR/FRAP. The proposed research aims to develop synthetically modified analogs of rapamycin that have selectively lost affinity for human FKBP and /or TOR/FRAP, stripping rapamycin of its side-effects in humans while maintaining fungicdal activity. Modification will be guided by the known crystal structure of rapamycin's complex with the human proteins, and the comparison with homologs from fungal pathogens. Results from binding and bioactivity assays will be used to optimize drug design. Rational redesign of a well characterized and potent molecule with a known target has many advantages over conventional screening approaches to antifungal drug discovery, including the potential to yield a clinical candidate directly and rapidly. PROPOSED COMMERCIAL APPLICATION: A broad-spectrum, orally active and well-tolerated antifungal would be a major challenger in the huge and growing market for antifungals (approximately US $4.2bn in 1995). There is particular potential application for systematic infections in AIDS patients, where resistance to current treatment is emerging. A fungus-selective rapamycin analog retaining rapamycin's attractive properties would have great clinical and commercial promise.
