Research Project
3498562
DESCRIPTION: (Adapted from the applicant's abstract) Recent reports have indicated that FK-506, a novel, highly potent immunosuppressant, is an effective agent for preventing organ transplant rejection in man which displays a different toxicity profile than cyclosporin A (CsA). A major FK-506 binding protein, inhibited by FKBP, has been shown to be a peptidyl-prolyl cis-trans isomerase that is specifically inhibited by FK-506. Prolyl isomerization activity is also displayed by the main cyclosporin A binding protein, cyclophilin, which is specifically inhibited by CsA. The study of this isomerization phenomenon and its exploitation to develop novel immunosuppressants for the treatment of autoimmune disease and organ transplant rejection has been hampered by technical difficulties in the isomerization assay. The immediate goal of the research described in this Phase I grant application is to develop specific, sensitive substrates for the assessment of peptidyl-porlyl cis-trans isomerase activity. Longer-range plans involve applying the understanding of isomerase-substrate interactions thus gained to the development of specific inhibitors of these enzymes. In this manner, the investigators plan to address the issue of whether catalysis of prolyl isomerization is causal for immunosuppression or is merely an adventitious phenomenon, possibly contributing to the toxicity of these compounds and to apply this knowledge to the development of future generations of immunomodulatory drugs.
