title: Structural requirements for the modulatory effect of 6-substituted pterins on interleukin 2 receptor binding.
abstract: (6R)-5,6,7,8-Tetrahydrobiopterin is produced by stimulated human T lymphocytes, and is known to affect various aspects of interleukin-2-directed T cell proliferation. Using an increased apparent affinity of interleukin 2 receptor to interleukin 2 as a measure of activity, this study explores whether other 6-substituted pterins might have the same effect, and what structural features are necessary for activity. Of the compounds tested, only the T-lymphocyte-derived (6R)-5,6,7,8-tetrahydrobiopterin was active. The diastereomeric (6S)-5,6,7,8-tetrahydrobiopterin was inactive, as were 7,8-dihydrobiopterin, sepiapterin, 5,6,7,8-tetrahydroneopterin, 6,7-dimethyl-5,6,7,8-tetrahydropterin and 6-hydroxymethylpterin. 7,8-Dihydroneopterin and neopterin were also found to be inactive. It follows that neither of these compounds participates in the feedback modulation of IL-2 receptor affinity, although both of them can be detected upon IFN-gamma stimulation of human monocytes/macrophages. A computer-based molecular modelling study of (6R)-5,6,7,8-tetrahydrobiopterin and (6R)-5,6,7,8-tetrahydroneopterin revealed substantial differences in overall shape between the two molecules, with certain features figuring prominently in the low-energy conformers of (6R)-5,6,7,8-tetrahydrobiopterin.
authors.affiliation: GSF-Institut für Klinische Molekular Biologie, München, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Ziegler
authors.forename: M
authors.initials: M
authors.lastname: Borchert
authors.forename: F
authors.initials: F
authors.lastname: Heaney
authors.forename: A P
authors.initials: AP
authors.lastname: Davis
authors.forename: P H
authors.initials: PH
authors.lastname: Boyle
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003198:Computer Simulation; D005246:Feedback; D015368:Human T-lymphotropic virus 1; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011622:Pterins / Q000737:chemistry / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000382:microbiology
chemical_list: D011622:Pterins; D015375:Receptors, Interleukin-2; D001708:Biopterins; C003402:sapropterin