A series of naphthopyrans was synthesized employing silica supported fluoroboric acid under solvent free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesised compounds were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have also been presented. Among the synthesised compounds, NP-17, NP-19, NP-20, NP-23, NP-24, NP-25 and NP-26 were the active inhibitors with an IC50 ranging from 4 to 17 μM. Compound NP-19 with a thiophenyl ring at position 1 emerged as the most potent xanthine oxidase inhibitor (IC50=4 μM) in comparison to allopurinol (IC50=11.10 μM) and febuxostat (IC50=0.025 μM). The basis of significant inhibition of xanthine oxidase by NP-19 was rationalized by its molecular docking at MTE binding site of xanthine oxidase.

1997-09-01·Journal of immunology (Baltimore, Md. : 1950)

Chimeric peptides: a new approach to enhancing the immunogenicity of peptides with low MHC class I affinity: application in antiviral vaccination.

Article

作者: Manuguerra, J C ; Kosmatopoulos, K ; Tourdot, S ; Cordopatis, P ; Magafa, V ; Bruley-Rosset, M ; Riché, N ; Vergnon, I ; Oukka, M

Recruitment of the CTL repertoire specific for subdominant epitopes that have a low MHC class I-binding affinity could be the way to achieve an efficient protective immunity against spontaneous tumors and viruses with high mutation rate. However, we have reported recently that subdominant peptides of influenza A Puerto Rico/8/34 (flu PR8) nucleoprotein (NP) with low Db affinity are only partially able to protect mice against lethal influenza infection. This seems to be due to their inability to recruit the specific CTL repertoire, and suggests that subdominant peptides could be used for vaccination only if they become highly immunogenic. In this work, we describe an approach that allows enhancement of the immunogenicity of every low affinity peptide presented by the Db molecule. It consists in producing chimeric peptides composed by amino acids from a high Db affinity peptide (NP366) in positions that interact with the MHC, and amino acids from low Db affinity nonimmunogenic influenza NP-derived peptides (NP17, NP97, NP330, and NP469) in positions that are exposed to the TCR. All chimeric peptides tested exhibited a high Db affinity and efficiently recruited the CTL repertoire specific for the corresponding low Db affinity peptide. Furthermore, vaccination with chimeric peptides that corresponded to subdominant NP17 and NP97 peptides induced a very potent anti-flu PR8 protective immunity.

1996-10-01·Journal of immunology (Baltimore, Md. : 1950)

Protection against lethal viral infection by vaccination with nonimmunodominant peptides.

Article

作者: Vergnon, I ; Livaditis, N ; Kosmatopoulos, K ; Manuguerra, J C ; Riche, N ; Cordopatis, P ; Oukka, M ; Tourdot, S

CTL response of H-2b mice to influenza PR8 virus is directed against the nucleoprotein (NP)-derived immunodominant 366-374 (NP366PR8) peptide presented by the Db molecule. However, NP has three nonimmunodominant peptides corresponding to the 17-25 (NP17), 55-63 (NP55), and 97-105 (NP97) sequences that have the Db consensus motifs and bind to the Db molecule with an intermediate (NP55) or low (NP17 and NP97) affinity. In a previous report, we have shown that NP55 peptide is naturally processed by infected cells. In the present work, we studied whether nonimmunodominant peptides can protect mice against viral infection. Antiviral protection was evaluated by measuring three parameters: survival after inoculation of a lethal dose of mouse-adapted PR8 virus, percentage of pulmonary lesions in surviving mice, and virus clearance from lungs of infected mice. Our results showed that immunization of B6 mice with nonimmunodominant peptides protected from PR8 virus infection, although less efficiently than immunization with the immunodominant NP366PR8 peptide. Protection was mediated by CD8 T cells. The efficacy of nonimmunodominant peptides correlated with their Db binding affinity; the low affinity binders NP17 and NP97 induced a weaker protection than the intermediate affinity binder NP55. A mixture of NP366PR8 and nonimmunodominant peptides gave a higher protection than NP366PR8 peptide alone. In conclusion, nonimmunodominant peptides protect against a viral infection with an efficacy that is proportional to their affinity for the restricting class I molecule.

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