SUBSTRATES FOR PEPTIDYL PROLYL CIS-TRANS ISOMERASE ASSAYS

RECENT REPORTS HAVE INDICATED THAT FK-506, A NOVEL, HIGHLY POTENT IMMUNOSUPPRESSANT, IS AN EFFECTIVE AGENT FOR PREVENTING ORGAN TRANSPLANT REJECTION IN HUMANS THAT DISPLAYS A DIFFERENT TOXICITY PROFILE THAN CYCLOSPORIN A (CSA). A MAJOR FK-506 BINDING PROTEIN, FKBP, HAS BEEN SHOWNTO BE A PEPTIDYL-PROLYL CIS-TRANS ISOMERASE THAT IS SPECIFICALLY INHIBITED BY FK-506. PROLYL ISOMERIZATION ACTIVITY IS ALSO DISPLAYED BY THE MAIN CSA 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 GOAL OF THIS RESEARCH IS TO DEVELOP SUBSTRATES FOR THE ASSESSMENT OF PEPTIDYL-PROLYL 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. THE RESEARCH WILL 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. THIS KNOWLEDGE WILL BE APPLIED TO THE DEVELOPMENT OF IMMUNOMODULATORY DRUGS.