Aryl ethynyl anthraquinones: a useful platform for targeting telomeric G-quadruplex structures

2,7-Diaryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, with good G-quadruplex/duplex selectivity

A novel DNA/histone H4 peptide complex detects autoantibodies in systemic lupus erythematosus sera

Background: The detection of anti-dsDNA antibodies is critical for the diagnosis and follow-up of systemic lupus erythematosus (SLE) patients. The presently available assays are characterized by a non-optimal specificity (solid phase assays) or sensitivity (Crithidia Luciliae immunofluorescence test (CLIFT)). To overcome the limits of CLIFT and solid phase chromatin assays, we explored the diagnostic potential of an assay based on plasmid DNA containing a highly bent fragment of 211 bp from Crithidia Luciliae minicircles, complexed with histone peptides. Methods: Electrically neutral complexes of PK201/CAT plasmid (PK) DNA and histone 4 (H4) peptides were evaluated by electromobility shift assay. Complexes of H4 peptides and PK were absorbed to the solid phase to detect specific immunoglobulin G (IgG) in sera. Sera from 109 SLE patients, 100 normal healthy subjects, and 169 disease controls were tested. Results: H4(14-34) containing the consensus sequence for DNA binding interacts with PK, retarding its migration. H4(14-34)/PK complexes were used to test sera by ELISA. Anti-H4-PK antibodies were detected in 56 % of SLE sera (more frequently in patients with skin or joint involvement) versus 5.9 % in disease controls; inhibition assays show that sera react with epitopes present on DNA or on the complex, not on the peptide. Antibody titer is correlated with European Consensus Lupus Activity Measurement (ECLAM) score and anti-complement component 1q (C1q) antibodies, negatively with C3 levels. Anti-H4-PK antibodies compared with CLIFT and solid phase dsDNA assays display moderate concordance. Conclusions: The H4/PK assay is a simple and reliable test which is useful for the differential diagnosis and evaluation of disease activity in SLE patients

Serological and genetic evidence for altered complement system functionality in systemic lupus erythematosus: Findings of the GAPAID consortium

Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of classswitched autoantibodies targeting nucleic acids

Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

n/

Synthèse de peptides contraints cycliques et linéaires

Récemment, beaucoup de recherches ont démontré l'importance des peptides dans le domaine de la chimie médicale. Le développement de médicaments basés sur la modification des peptides, mimétiques des protéines natives, est une cible très importante. La synthèse de peptides contraints est une stratégie très efficace pour des études structure-activité ayant la finalité de caractériser les sites actifs des protéines. Au cours de cette thèse, les peptides ont été modifiés par introduction de différentes contraintes. Dans une première partie de ces études, une série d'acides aminés non naturels contraintes ont été synthétisées. Les acides aminés ont été introduits dans la séquence peptidique de l'antagoniste puissant de la bradykinine HOE 140. Des analogues de ce peptide ont été synthétisés en phase solide et des tests biologiques ont été effectués. Au cours de la deuxième partie de la thèse une stratégie efficace de synthèse de cyclopeptides contraints en phase solide a été développée.Many researches have recently demonstrated the importance of peptides for medicinal chemistry. The development of new drugs based on peptide modification is an important goal, as peptides can mimic proteins. The synthesis of constrained peptides represents a very efficient strategy for structure-activity relationship studies, in order to characterize the protein active site. During this thesis, peptides were modified introducing different constraints. In the first part of these studies, a series of unnatural amino acids were synthesized. These amino acids were introduced in the peptide sequence of the potent BK antagonist HOE 140. These peptide analogues were synthesized by a solid-phase approach and were then tested for their biological activity. In the second part of this thesis an efficient solid-phase strategy for the synthesis of constrained cyclopeptides was set up.CERGY PONTOISE-BU Neuville (951272102) / SudocSudocFranceF

Aryl ethynyl anthraquinones: a useful platform for targeting telomeric G-quadruplex structures

Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking. Both the binding properties and G-quadruplex vs. duplex selectivity are controlled by the structures of the aryl ethynyl moietie