Assessment of the conformational implications of chemical modification is an important aspect of analogue design. A new procedure, the assessment of conformational mimicry, which determines the percentage of sterically accessible conformations for the parent compound also available to the analogue, is used to show that 88% of the conformers allowed for the cis amide bond are also available to peptides in which the amide bond is replaced by a 1,5-disubstituted tetrazole ring that locks the amide bond in the cis conformer. This analysis was made possible by the crystal structure of a cyclic dipeptide, cyclo[l-Phe-i/'(CN4)-L-Ala], determined in this paper. The crystals of the diketopiperazine analogue are monoclinic, space group P2\/c, with cell parameters a = 11.677 (1), b = 7.742 (1), c = 13.086 (1) A; /? = 93.39 (1)°; Z = 4; and = 1.368 g cm-3. The tetrazole ring system is planar with all five torsional angles equal to 0°. The diketopiperazine ring system is nearly planar, and the phenylalanine ring adopts the flagpole orientation over the cyclic dipeptide. A procedure for the preparation of this class of peptide analogues by synthetic routes avoiding racemization of the amino acids of the starting dipeptide is demonstrated. The tetrazole ring provides, therefore, a synthetic probe for the role of cis-trans isomerism of A'-alkylamide bonds, such as that of proline, in molecular recognition.Replacement of the amide bond by surrogates to enhance metabolic stability and/or probe receptor specificity has become an increasingly important topic of research1 as the central biological role of peptides as chemical effectors becomes more understood. Proline occupies a special role among those amino acids

Background: Golgi is a potential target for cancer treatment, but no inhibitor became an anticancer drug.Results: Using a unique bioinformatics approach, we identified a novel Golgi inhibitor, AMF-26, targeting Arf1 activation and possessing potent antitumor activity.Conclusion: AMF-26 is a promising new anticancer drug lead.Significance: Our data indicate that Arf1 activation is a promising target for cancer treatment.

Several structurally unrelated scaffolds of the Rho kinase inhibitor were designed using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. A docking simulation using the ligand-binding pocket of the Rho kinase model helped to comprehensively understand and to predict the structure-activity relationship of the inhibitors. This understanding was useful for developing new Rho kinase inhibitors of higher potency and selectivity. We identified several potent platforms for developing the Rho kinase inhibitors, namely, pyridine, 1H-indazole, isoquinoline, and phthalimide.

The structural basis for the T cell response to glycolipid antigens (Ags) remains poorly understood. T lymphocytes autoreactive for mouse CD1 (mCD1.1) or reactive for the glycosphingolipid ␣-galactosylceramide (␣-GalCer) presented by mCD1.1 have been described previously. In this paper it is shown that mutations at the top of the ␣ helices and in the bottom of the Ag-binding groove can disrupt both mCD1.1 autoreactivity and ␣-GalCer recognition. The locations of the positions that affect T cell responses indicate that recognition of mCD1.1 is not likely to be unconventional or superantigen-like. Furthermore, the effects of the bottom of the pocket mutation suggest that the autoreactive response could require an autologous ligand, and they indicate that ␣-GalCer binds to the groove of mCD1.1, most likely with the shorter 18-carbon hydrophobic chain in the A pocket. Natural killer T cell hybridomas with identical T cell antigen receptor (TCR) ␣ chains and different ␤ chains respond differently to ␣-GalCer presented by mCD1.1 mutants. This finding indicates a role for TCR ␤ in defining natural killer T cell specificity, despite the more restricted diversity of the ␣ chains in these cells. Overall, the data are consistent with a mode of lipoglycan recognition similar to that proposed for glycopeptides, in which the TCR ␣ and ␤ chains survey a surface composed of both mCD1.1 and the carbohydrate portion of ␣-GalCer.

No abstract