SCIENCE/TECHNOLOGY
Immunosuppressants' Target Molecule Found The common molecular target of two drugs that suppress the human im mune system has been discovered by two collaborating research groups [Cell 66, 807 (1991)]. This finding may explain why cyclosporin A and FK506, which have dissimilar struc tures, have such similar immunosup pressive effects. It also adds to scien tists' understanding of how immuno suppressive or other "messages" are transmitted sequentially from cell surfaces through the cytoplasm to cell nuclei for action. This finding that immunosuppres sive drugs bring together their bind ing proteins and a common target molecule may also aid in the search for a natural, endogenous immuno suppressant. Cyclosporin A and FK506 are products of mold fermen tation broths. They do not occur in human tissues. But their effectiveness suggests that they are mimicking one or more endogenous human factors yet undiscovered. If found, such en dogenous factors could be produced in the laboratory and developed to suppress the immune system for or gan transplants in ways that match the body's own immune modulation. They might also be used to treat such autoimmune diseases as diabetes and rheumatoid arthritis. Indeed, cyclosporin has demon
strated some benefit to sufferers of rheumatoid and chronic juvenile ar thritis and inflammatory eye disease in preliminary studies. The drug caused kidney toxicity in one third of patients, however. And the relapse rate after stopping cyclosporin was high. Thus, in view of the apparent need to administer such an agent for patients' lifetimes, there would be great interest to study an endoge nous immunosuppressant that might lack side effects of the mold-derived compound. One team, at Stanford University's School of Medicine, consists of im munology professor Irving L. Weissman and graduate student Jeff Fried man. The other team, at Harvard University, consists of organic chem istry professor Stuart L. Schreiber, postdoctoral fellows Jun Liu and Jesse D. Farmer Jr., and William S. Lane, who heads the protein microsequencing facility at Harvard. Their work was supported by the National Institute of General Medi cal Sciences, Damon Runyon-Walter Winchell Cancer Fund, and the American Cancer Society. In a logical, elegant series of pro tein binding, displacement, identifi cation, sequencing, and enzyme as say studies, the Stanford and Har vard groups traced out a probable
sequence of events. Cyclosporin A, a macrocyclic peptide, binds to the protein cyclophilin. FK506, a macrocyclic lactone-lactam, binds to what is called FK506-binding protein (FKBP). Such immunosuppressantbinding proteins are known collec tively as immunophilins. Each drug binds so that part of the macrocycle is buried in a pocket of its immunophilin, and the rest, an effector domain, is presented to the outside environment (C&EN, May 20, page 25). When a drug-immunophilin complex encounters the com mon target protein calcineurin, the exposed effector domain binds to it, aided by the calcium-binding pro tein calmodulin and calcium or magnesium ions. Thus, cyclosporin A or FK506 seems to function as the dab of molecular glue that joins its immunophilin to calcineurin. Calcineurin is an enzyme whose phosphatase activity is mediated by calmodulin and calcium. It is a com plex of two subunits, calcineurin A and B. But in the pentapartite com plex, drug-immunophilin-calmodulin-calcineurin A and B, the phos phatase activity of calcineurin is in hibited. The inhibition of phosphatase ac tivity may or may not be crucial to the immunosuppressant function. At any rate, the pentapartite com plex somehow exerts two effects next. One effect is to stop translation of deoxyribonucleic acid in nuclei of T-lymphocytes, which are key fac tors in the immune system. The oth er effect is to prevent immunoglob ulin Ε from stimulating release of secretory granules from mast cells. These granules contain mediators of tissue inflammation like histamine. The Stanford and Harvard investi gators emphasize that the present ex periments were done in vitro. Their future work includes biological stud ies to determine whether calcineurin is the target in vivo and thus the key to modulation of signals to T-lym phocytes and mast cells. Stephen Stinson August 26, 1991 C&EN
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