The potent immunosuppressive cyclosporin FR901459 inhibits the human P-glycoprotein and formyl peptide receptor functions

By sequestering cytosolic calcineurin into a molecular complex with cycloph iIin and its consequent T-cel dysfunction, some cyclosporins, such as CsA a nd FR901459 ([Thr(2)-Leu(5)-Leu(10)]-CsA), display potent immunosuppressive activity. Independently on this property, cyclosporins may display one or more other biological activities mediated by interaction with cell surface glycoproteins. Several cyclosporins inhibit the function of human MDR1-enco ded P-glycoprotein (Pgp), a flippase known to cause cancer multidrug resist ance, but also expressed by some normal immunocompetent cells and by normal epithelial cells which control drug bioavailability in vivo. CsA is known to be a potent Pgp inhibitor with a 3.2 mu M IC50 in an assay where the mos t potent derivative SDZ PSC 833 gives a 0.49 mu M IC50. FR901459 is now sho wn to be a good Pgp inhibitor, being 2-fold weaker only (IC50 of 6 mu M) th an CsA. Some cyclosporins may also inhibit the function of the human FPR1-e ncoded formyl peptide receptor (FPR), a chemotactic receptor whose absence is known to impair antibacterial immunity. Yet this inhibition is very weak for all, but one of them, CsH, whose 0.15 mu M IC50 makes it a much more p otent FPR inhibitor than CsA (IC50 >10 mu M in the same assay). FR901459 is now shown to be a very potent inhibitor of FPR function (IC50 of 0.6 mu M) . Since CsH shows little Pgp-inhibitory activity and has no known immunosup pressive activity, FR901459 displays a unique pharmacological profile: like CsA, it inhibits T-cell function; less than CsA, it can inhibit Pgp functi on on selected leukocyte subsets and on epithelial barriers known to contro l drug bioavailability; however, much more efficiently than CsA, it can inh ibit the FPR function, a receptor involved in some leukocytic inflammatory responses to chemotactic peptides.