Serge BOUAZIZ
@citcom.cnrs.fr
Université Paris Cité - UFR de pharmacie CiTCoM - UMR 8038 CNRS
Scopus Publications
Scopus Publications
Aurore De Rache, Julien Marquevielle, Serge Bouaziz, Brune Vialet, Marie-Line Andreola, Jean-Louis Mergny, and Samir Amrane
Elsevier BV
Steven R. LaPlante, Pascale Coric, Serge Bouaziz, and Tanos C.C. França
Elsevier BV
Elodie Bosc, Julie Anastasie, Feryel Soualmia, Pascale Coric, Ju Youn Kim, Lily Q. Wang, Gullen Lacin, Kaitao Zhao, Ronak Patel, Eric Duplus,et al.
Springer Science and Business Media LLC
AbstractCaspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~5,500,000 M−1 s−1), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of Cα at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with β-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.
Guillaume Le Guyader, Bernard Do, Ivo B. Rietveld, Pascale Coric, Serge Bouaziz, Jean-Michel Guigner, Philippe-Henri Secretan, Karine Andrieux, and Muriel Paul
MDPI AG
Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2–8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.
Xiao Wang, Xiaowei Chen, Sylvie Nonin‐Lecomte, and Serge Bouaziz
Wiley
AbstractDetergent‐soluble proteins (DSPs) are commonly dissolved in lipid buffers for NMR experiments, but the huge lipid proton signal prevents recording of high‐quality spectra. The use of costly deuterated lipids is thus required to replace nondeuterated ones. With conventional methods, detergents like dodecylphosphocholine (DPC) cannot be fully exchanged due to their high binding affinity to hydrophobic proteins. We propose an original and simple protocol which combines the use of acetonitrile, dialysis and lyophilization to disrupt the binding of lipids to the protein and allow their indirect replacement by their deuterated equivalents, while maintaining the native structure of the protein. Moreover, by this protocol, the detergent‐to‐protein molar ratio can be controlled as it challenges the protein structure. This protocol was applied to solubilize the Vpx protein that was followed upon addition of DPC‐d38 by 1H‐15N SOFAST‐HMQC spectra and the best detergent‐to‐DSPs molar ratio was obtained for structural studies.
Rafael Gomes Von Borowski, Sophie Chat, Rafael Schneider, Sylvie Nonin-Lecomte, Serge Bouaziz, Emmanuel Giudice, Aline Rigon Zimmer, Simone Cristina Baggio Gnoatto, Alexandre José Macedo, and Reynald Gillet
American Society for Microbiology
Pathogenic biofilms are a global health care concern, as they can cause extensive antibiotic resistance, morbidity, mortality, and thereby substantial economic loss. So far, no effective treatments targeting the bacteria in biofilms have been developed.
Xiaowei Chen, Pascale Coric, and Serge Bouaziz
Springer Science and Business Media LLC
Xiaowei Chen, Pascale Coric, Valery Larue, Serge Turcaud, Xiao Wang, Sylvie Nonin-Lecomte, and Serge Bouaziz
Elsevier BV
Nathalie Chazal, Hugues de Rocquigny, Philippe Roussel, Serge Bouaziz, Françoise Barré-Sinoussi, Jean-François Delfraissy, and Jean-Luc Darlix
Springer Science and Business Media LLC
Léa El Khoury, Frédéric Célerse, Louis Lagardère, Luc-Henri Jolly, Etienne Derat, Zeina Hobaika, Richard G. Maroun, Pengyu Ren, Serge Bouaziz, Nohad Gresh,et al.
American Chemical Society (ACS)
A. Sami Saribas, Pascale Coric, Serge Bouaziz, and Mahmut Safak
Wiley
AbstractPolyomavirus family consists of a highly diverse group of small DNA viruses. The founding family member (MPyV) was first discovered in the newborn mouse in the late 1950s, which induces solid tumors in a wide variety of tissue types that are the epithelial and mesenchymal origin. Later, other family members were also isolated from a number of mammalian, avian and fish species. Some of these viruses significantly contributed to our current understanding of the fundamentals of modern biology such as transcription, replication, splicing, RNA editing, and cell transformation. After the discovery of first two human polyomaviruses (JC virus [JCV] and BK virus [BKV]) in the early 1970s, there has been a rapid expansion in the number of human polyomaviruses in recent years due to the availability of the new technologies and brought the present number to 14. Some of the human polyomaviruses cause considerably serious human diseases, including progressive multifocal leukoencephalopathy, polyomavirus‐associated nephropathy, Merkel cell carcinoma, and trichodysplasia spinulosa. Emerging evidence suggests that the expression of the polyomavirus genome is more complex than previously thought. In addition to encoding universally expressed regulatory and structural proteins (LT‐Ag, Sm t‐Ag, VP1, VP2, and VP3), some polyomaviruses express additional virus‐specific regulatory proteins and microRNAs. This review summarizes the recent advances in polyomavirus genome expression with respect to the new viral proteins and microRNAs other than the universally expressed ones. In addition, a special emphasis is devoted to the recent structural and functional discoveries in the field of polyomavirus agnoprotein which is expressed only by JCV, BKV, and simian virus 40 genomes.
Lei Wang, Pascale Coric, Sylvain Broussy, Rossella Di Stasi, Lingyu Zhou, Luca D. D'Andrea, Lili Ji, Michel Vidal, Serge Bouaziz, and Wang-Qing Liu
Elsevier BV
Eric Mauro, Paul Lesbats, Delphine Lapaillerie, Stephane Chaignepain, Benoit Maillot, Oyindamola Oladosu, Xavier Robert, Francesca Fiorini, Bruno Kieffer, Serge Bouaziz,et al.
Oxford University Press (OUP)
Abstract The integration of the retroviral genome into the chromatin of the infected cell is catalysed by the integrase (IN)•viral DNA complex (intasome). This process requires functional association between the integration complex and the nucleosomes. Direct intasome/histone contacts have been reported to modulate the interaction between the integration complex and the target DNA (tDNA). Both prototype foamy virus (PFV) and HIV-1 integrases can directly bind histone amino-terminal tails. We have further investigated this final association by studying the effect of isolated histone tails on HIV-1 integration. We show here that the binding of HIV-1 IN to a peptide derived from the H4 tail strongly stimulates integration catalysis in vitro. This stimulation was not observed with peptide tails from other variants or with alpha-retroviral (RAV) and spuma-retroviral PFV integrases. Biochemical analyses show that the peptide tail induces both an increase in the IN oligomerization state and affinity for the target DNA, which are associated with substantial structural rearrangements in the IN carboxy-terminal domain (CTD) observed by NMR. Our data indicate that the H4 peptide tail promotes the formation of active strand transfer complexes (STCs) and support an activation step of the incoming intasome at the contact of the histone tail.
Aymeric Neyret, Bernard Gay, Anaïs Cransac, Laurence Briant, Pascale Coric, Serge Turcaud, Philippe Laugâa, Serge Bouaziz, and Nathalie Chazal
Elsevier BV
Hesna Kara, Nathalie Chazal, and Serge Bouaziz
Bentham Science Publishers Ltd.
Uracil-DNA glycosylase-2 (UNG2) is a DNA repair protein that removes uracil from single and double-stranded DNA through a basic excision repair process. UNG2 is packaged into new virions by interaction with integrase (IN) and is needed during the early stages of the replication cycle. UNG2 appears to play both a positive and negative role during HIV-1 replication; UNG2 improves the fidelity of reverse transcription but the nuclear isoform of UNG2 participates in the degradation of cDNA and the persistence of the cellular genome by repairing its uracil mismatches. In addition, UNG2 is neutralized by Vpr, which redirects it to the proteasome for degradation, suggesting that UNG2 may be a new cellular restriction factor. So far, we have not understood why HIV-1 imports UNG2 via its IN and why it causes degradation of endogenous UNG2 by redirecting it to the proteasome via Vpr. In this review, we propose to discuss the ambiguous role of UNG2 during the HIV-1 replication cycle.
Hesna Kara, Luc Ponchon, and Serge Bouaziz
Springer Science and Business Media LLC
Lei Wang, Pascale Coric, Kexin Zhu, Wang-Qing Liu, Michel Vidal, Serge Bouaziz, and Sylvain Broussy
Royal Society of Chemistry (RSC)
Macrocyclic peptides mimic tight “non-classical” α-turn type II-αLS found in proteins, as shown by spectroscopic and computational analysis of their equilibrating conformations.
Pascale Coric, A. Sami Saribas, Magid Abou‐Gharbia, Wayne Childers, Jon H. Condra, Martyn K. White, Mahmut Safak, and Serge Bouaziz
Wiley
ABSTRACTAgnoprotein is an important regulatory protein of the human polyoma JC virus (JCV) and plays critical roles during the viral replication cycle. It forms highly stable dimers and oligomers through its Leu/Ile/Phe‐rich domain, which is important for the stability and function of the protein. We recently resolved the partial 3D structure of this protein by NMR using a synthetic peptide encompassing amino acids Thr17 to Gln52, where the Leu/Ile/Phe‐ rich region was found to adopt a major alpha‐helix conformation spanning amino acids 23–39. Here, we report the resolution of the 3D structure of full‐length JCV agnoprotein by NMR, which not only confirmed the existence of the previously reported major α‐helix domain at the same position but also revealed the presence of an additional minor α‐helix region spanning amino acid residues Leu6 to lys13. The remaining regions of the protein adopt an intrinsically unstructured conformation. J. Cell. Biochem. 118: 3268–3280, 2017. © 2017 Wiley Periodicals, Inc.
Divakaran Murugesapillai, Serge Bouaziz, L. James Maher, Nathan E. Israeloff, Craig E. Cameron, and Mark C. Williams
Royal Society of Chemistry (RSC)
We obtain accurate three-dimensional persistence length measurements for DNA and DNA–protein complexes using liquid AFM imaging, validated by optical tweezers.
Jean-François Gaucher, Marie Reille-Seroussi, Nathalie Gagey-Eilstein, Sylvain Broussy, Pascale Coric, Bili Seijo, Marie-Bernard Lascombe, Benoit Gautier, Wang-Quing Liu, Florent Huguenot,et al.
Public Library of Science (PLoS)
Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the presence of Zn2+, Co2+ or Cu2+ as a dimer that forms via metal-ion interactions and interlocked hydrophobic surfaces. SAXS, NMR and size exclusion chromatography analyses confirm the formation of this dimer in solution in the presence of Co2+, Cd2+ or Cu2+. Since the metal-induced dimerization masks the VEGFs binding surface, we investigated the ability of metal ions to displace the VEGF-A binding to hVEGFR1: using a competition assay, we evidenced that the metals displaced the VEGF-A binding to hVEGFR1 extracellular domain binding at micromolar level.
Kévin Cottet, Bin Xu, Pascale Coric, Serge Bouaziz, Sylvie Michel, Michel Vidal, Marie-Christine Lallemand, and Sylvain Broussy
American Chemical Society (ACS)
Natural products guttiferone A, hyperforin, and aristoforin were able to inhibit or increase SIRT1 catalytic activity, depending on protein concentration and presence of detergent. On the basis of NMR data for guttiferone A, we demonstrated that the aggregation state of the natural product played a crucial role for its interaction with the enzyme. These results are useful to interpret future in vitro structure-activity relationship studies on these natural products in the quest of their biological target(s).
A. Sami Saribas, Pascale Coric, Anahit Hamazaspyan, William Davis, Rachael Axman, Martyn K. White, Magid Abou‐Gharbia, Wayne Childers, Jon H. Condra, Serge Bouaziz,et al.
Wiley
Agnoprotein is an important regulatory protein of polyomaviruses, including JCV, BKV, and SV40. In the absence of its expression, these viruses are unable to sustain their productive life cycle. It is a highly basic phosphoprotein that localizes mostly to the perinuclear area of infected cells, although a small amount of the protein is also found in nucleus. Much has been learned about the structure and function of this important regulatory protein in recent years. It forms highly stable dimers/oligomers in vitro and in vivo through its Leu/Ile/Phe‐rich domain. Structural NMR studies revealed that this domain adopts an alpha‐helix conformation and plays a critical role in the stability of the protein. It associates with cellular proteins, including YB‐1, p53, Ku70, FEZ1, HP1α, PP2A, AP‐3, PCNA, and α‐SNAP; and viral proteins, including small t antigen, large T antigen, HIV‐1 Tat, and JCV VP1; and significantly contributes the viral transcription and replication. This review summarizes the recent advances in the structural and functional properties of this important regulatory protein. J. Cell. Physiol. 231: 2115–2127, 2016. © 2016 Wiley Periodicals, Inc.
Phuhai Nguyen, Nassima Oumata, Flavie Soubigou, Justine Evrard, Nathalie Desban, Pascale Lemoine, Serge Bouaziz, Marc Blondel, and Cécile Voisset
Elsevier BV
Pascale Coric, A. Sami Saribas, Magid Abou-Gharbia, Wayne Childers, Martyn K. White, Serge Bouaziz, and Mahmut Safak
American Society for Microbiology
Volume 88, no. 12, p. [6556–6575][1], 2014. Page 6556, abstract, line 5: “Glu55” should read “Gln52.”
Page 6556, importance, line 4: “Q54” should read “Q52.”
Page 6557, column 2, second full paragraph, line 3: “Glu54” should read “Gln52.”
The authors regret these errors
Pascale Coric, A. Sami Saribas, Magid Abou-Gharbia, Wayne Childers, Martyn K. White, Serge Bouaziz, and Mahmut Safak
American Society for Microbiology
ABSTRACT Agnoprotein is a small multifunctional regulatory protein required for sustaining the productive replication of JC virus (JCV). It is a mostly cytoplasmic protein localizing in the perinuclear area and forms highly stable dimers/oligomers through a Leu/Ile/Phe-rich domain. There have been no three-dimensional structural data available for agnoprotein due to difficulties associated with the dynamic conversion from monomers to oligomers. Here, we report the first nuclear magnetic resonance (NMR) structure of a synthetic agnoprotein peptide spanning amino acids Thr17 to Glu55 where Lys23 to Phe39 encompassing the Leu/Ile/Phe-rich domain forms an amphipathic α-helix. On the basis of these structural data, a number of Ala substitution mutations were made to investigate the role of the α-helix in the structure and function of agnoprotein. Single L29A and L36A mutations exhibited a significant negative effect on both protein stability and viral replication, whereas the L32A mutation did not. In addition, the L29A mutant displayed a highly nuclear localization pattern, in contrast to the pattern for the wild type (WT). Interestingly, a triple mutant, the L29A+L32A+L36A mutant, yielded no detectable agnoprotein expression, and the replication of this JCV mutant was significantly reduced, suggesting that Leu29 and Leu36 are located at the dimer interface, contributing to the structure and stability of agnoprotein. Two other single mutations, L33A and E34A, did not perturb agnoprotein stability as drastically as that observed with the L29A and L36A mutations, but they negatively affected viral replication, suggesting that the role of these residues is functional rather than structural. Thus, the agnoprotein dimerization domain can be targeted for the development of novel drugs active against JCV infection. IMPORTANCE Agnoprotein is a small regulatory protein of JC virus (JCV) and is required for the successful completion of the viral replication cycle. It forms highly stable dimers and oligomers through its hydrophobic (Leu/Ile/Phe-rich) domain, which has been shown to play essential roles in the stability and function of the protein. In this work, the Leu/Ile/Phe-rich domain has been further characterized by NMR studies using an agnoprotein peptide spanning amino acids T17 to Q54. Those studies revealed that the dimerization domain of the protein forms an amphipathic α-helix. Subsequent NMR structure-based mutational analysis of the region highlighted the critical importance of certain amino acids within the α-helix for the stability and function of agnoprotein. In conclusion, this study provides a solid foundation for developing effective therapeutic approaches against the dimerization domain of the protein to inhibit its critical roles in JCV infection.