Structural requirements for the modulatory effect of 6-substituted pterins on interleukin 2 receptor binding.
(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.
Ziegler
I
I
GSF-Institut für Klinische Molekular Biologie, München, Germany.
Borchert
M
M
Heaney
F
F
Davis
A P
AP
Boyle
P H
PH
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
D011622:Pterins; D015375:Receptors, Interleukin-2; D001708:Biopterins; C003402:sapropterin