Lymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P(1)), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P(1) receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P(1) antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P(1) antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P(1) receptor antagonism and to differentiate the effects from those of S1P(1) agonists.

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The synthetic oligopeptide I undergoes a spontaneous, reversible transition from an α‐helix to a β‐sheet structure in mixtures of 45% 2,2,2‐trifluoroethanol and 55% H2O. The amphiphilic oligopeptide 1 and two isomers were expressly designed for this investigation. Such peptides, which can exist in several conformations, might find application as “switches” in the de novo design of artificial proteins. equation image

A new general strategy for the construction of artificial proteins with predetermined tertiary structure is presented. Amphiphilic a -helix and 8-sheet-forming oligopeptides are assembled on a multifunctional template molecule which directs the peptide blocks to adopt characteristic folding topologies. The design, synthesis, and conformational properties of these template-assembled synthetic proteins (TASP) are exemplified for pep-, ahelix-bundle-and /I-barrel-like tertiary structures using specially designed oligopeptides as template molecules. In contrast to linear polypeptide chains of comparable molecular weights, these conceptually novel macromolecules are readily accessible to chemical synthesis and exhibit excellent solubility in a number of solvents. Experimental evidence is provided for a template-induced intramolecular folding to secondary and tertiary structures in aqueous solutions. This approach opens new prospects for the chemical construction of biomacromolecules with tailormade structural and functional properties.