76 results on '"Karoyan P"'
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52. ChemInform Abstract: One‐Pot Synthesis of β‐Amino Acid Derivatives via Addition of Bis(O‐Silyl) Ketene Acetals on Iminium Salts.
- Author
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Moumne, Roba, Denise, Bernard, Parlier, Andree, Lavielle, Solange, Rudler, Henri, and Karoyan, Philippe
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 2008
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53. Substituted Prolines: Syntheses and Applications in Structure—Activity Relationship Studies of Biologically Active Peptides
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Karoyan, Philippe, Sagan, Sandrine, Lequin, Olivier, Quancard, Jean, Lavielle, Solange, and Chassaing, Gerard
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
- Published
- 2006
- Full Text
- View/download PDF
54. ChemInform Abstract: Asymmetric Synthesis of 3‐Alkyl Substituted Prolines by Alkylation of a Chiral Sulfone.
- Author
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Karoyan, Philippe and Chassaing, Gerard
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 2002
- Full Text
- View/download PDF
55. ChemInform Abstract: Short Asymmetric Synthesis of (2S,3S)‐ and (2S,3R)‐3‐Prolinoglutamic Acids: 2‐Carboxy‐3‐pyrrolidine‐acetic Acid (CPAA).
- Author
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Karoyan, Philippe and Chassaing, Gerard
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 2002
- Full Text
- View/download PDF
56. PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.
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Baron L, Hadjerci J, Thoidingjam L, Plays M, Bucci R, Morris N, Müller S, Sindikubwabo F, Solier S, Cañeque T, Colombeau L, Blouin CM, Lamaze C, Puisieux A, Bono Y, Gaillet C, Laraia L, Vauzeilles B, Taran F, Papot S, Karoyan P, Duval R, Mahuteau-Betzer F, Arimondo P, Cariou K, Guichard G, Micouin L, Ethève-Quelquejeu M, Verga D, Versini A, Gasser G, Tang C, Belmont P, Linkermann A, Bonfio C, Gillingham D, Poulsen T, Di Antonio M, Lopez M, Guianvarc'h D, Thomas C, Masson G, Gautier A, Johannes L, and Rodriguez R
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- Humans, Paris, Biology
- Abstract
This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie., (© 2023 Wiley-VCH GmbH.)
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- 2023
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57. PKHB1 Tumor Cell Lysate Induces Antitumor Immune System Stimulation and Tumor Regression in Syngeneic Mice with Tumoral T Lymphoblasts.
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Martínez-Torres AC, Calvillo-Rodríguez KM, Uscanga-Palomeque AC, Gómez-Morales L, Mendoza-Reveles R, Caballero-Hernández D, Karoyan P, and Rodríguez-Padilla C
- Abstract
Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. Currently, treatment options for patients with relapsed and refractory ALL mostly rely on immunotherapies. However, hematological cancers are commonly associated with a low immunogenicity and immune tolerance, which may contribute to leukemia relapse and the difficulties associated with the development of effective immunotherapies against this disease. We recently demonstrated that PKHB1, a TSP1-derived CD47 agonist peptide, induces immunogenic cell death (ICD) in T cell ALL (T-ALL). Cell death induced by PKHB1 on T-ALL cell lines and their homologous murine, L5178Y-R (T-murine tumor lymphoblast cell line), induced damage-associated molecular patterns (DAMPs) exposure and release. Additionally, a prophylactic vaccination with PKHB1-treated L5178Y-R cells prevented tumor establishment in vivo in all the cases. Due to the immunogenic potential of PKHB1-treated cells, in this study we assessed their ability to induce antitumor immune responses ex vivo and in vivo in an established tumor. We first confirmed the selectivity of cell death induced by PKBH1 in tumor L5178Y-R cells and observed that calreticulin exposure increased when cell death increased. Then, we found that the tumor cell lysate (TCL) obtained from PKHB1-treated L5178YR tumor cells (PKHB1-TCL) was able to induce, ex vivo , dendritic cells maturation, cytokine production, and T cell antitumor responses. Finally, our results show that in vivo , PKHB1-TCL treatment induces tumor regression in syngeneic mice transplanted with L5178Y-R cells, increasing their overall survival and protecting them from further tumor establishment after tumor rechallenge. Altogether our results highlight the immunogenicity of the cell death induced by PKHB1 activation of CD47 as a potential therapeutic tool to overcome the low immunogenicity and immune tolerance in T-ALL.
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- 2019
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58. Small AntiMicrobial Peptide With in Vivo Activity Against Sepsis.
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Boullet H, Bentot F, Hequet A, Ganem-Elbaz C, Bechara C, Pacreau E, Launay P, Sagan S, Jolivalt C, Lacombe C, Moumné R, and Karoyan P
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- Amino Acids chemistry, Animals, Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Antimicrobial Cationic Peptides chemistry, Antimicrobial Cationic Peptides pharmacology, Disease Models, Animal, Drug Design, Gram-Negative Bacteria drug effects, Gram-Positive Bacteria drug effects, Humans, Mice, Microbial Sensitivity Tests, Molecular Mimicry, Proteolysis, Sepsis etiology, Sepsis microbiology, Anti-Infective Agents administration & dosage, Anti-Infective Agents chemical synthesis, Antimicrobial Cationic Peptides administration & dosage, Antimicrobial Cationic Peptides chemical synthesis, Sepsis drug therapy
- Abstract
Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic β-amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice., Competing Interests: Declare conflicts of interest or state “The authors declare no conflict of interest.”
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- 2019
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59. 2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology.
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Lucchino M, Billet A, Versini A, Bavireddi H, Dasari BD, Debieu S, Colombeau L, Cañeque T, Wagner A, Masson G, Taran F, Karoyan P, Delepierre M, Gaillet C, Houdusse A, Britton S, Schmidt F, Florent JC, Belmont P, Monchaud D, Cossy J, Thomas C, Gautier A, Johannes L, and Rodriguez R
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- Humans, Paris, Biology, Chemistry
- Abstract
Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2019
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60. Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope.
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Dorgham K, Pietrancosta N, Affoune A, Lucar O, Bouceba T, Chardonnet S, Pionneau C, Piesse C, Sterlin D, Guardado-Calvo P, Karoyan P, Debré P, Gorochov G, and Vieillard V
- Subjects
- Animals, Antibodies, Monoclonal immunology, Bacteriophages immunology, HIV-1, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Docking Simulation, Neutralization Tests, Peptides administration & dosage, Peptides immunology, Protein Binding drug effects, Antibodies, Neutralizing immunology, Epitope Mapping methods, Epitopes immunology, HIV Antibodies immunology, HIV Envelope Protein gp41 immunology
- Abstract
The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties.
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- 2019
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61. Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer.
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Bellier J, Nokin MJ, Lardé E, Karoyan P, Peulen O, Castronovo V, and Bellahcène A
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- Animals, Diabetes Complications complications, Diabetes Complications mortality, Diabetes Complications pathology, Humans, Hyperglycemia complications, Hyperglycemia metabolism, Hyperglycemia mortality, Hyperglycemia pathology, Meta-Analysis as Topic, Neoplasms complications, Neoplasms mortality, Neoplasms pathology, Pyruvaldehyde metabolism, Up-Regulation drug effects, Diabetes Complications metabolism, Glycation End Products, Advanced metabolism, Neoplasms metabolism, Oxidative Stress drug effects, Pyruvaldehyde pharmacology
- Abstract
Diabetes is one of the most frequent diseases throughout the world and its incidence is predicted to exponentially progress in the future. This metabolic disorder is associated with major complications such as neuropathy, retinopathy, atherosclerosis, and diabetic nephropathy, the severity of which correlates with hyperglycemia, suggesting that they are triggered by high glucose condition. Reducing sugars and reactive carbonyl species such as methylglyoxal (MGO) lead to glycation of proteins, lipids and DNA and the gradual accumulation of advanced glycation end products (AGEs) in cells and tissues. While AGEs are clearly implicated in the pathogenesis of diabetes complications, their potential involvement during malignant tumor development, progression and resistance to therapy is an emerging concept. Meta-analysis studies established that patients with diabetes are at higher risk of developing cancer and show a higher mortality rate than cancer patients free of diabetes. In this review, we highlight the potential connection between hyperglycemia-associated AGEs formation on the one hand and the recent evidence of pro-tumoral effects of MGO stress on the other hand. We also discuss the marked interest in anti-glycation compounds in view of their strategic use to treat diabetic complications but also to protect against augmented cancer risk in patients with diabetes., (Copyright © 2019. Published by Elsevier B.V.)
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- 2019
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62. CD47 agonist peptide PKHB1 induces immunogenic cell death in T-cell acute lymphoblastic leukemia cells.
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Uscanga-Palomeque AC, Calvillo-Rodríguez KM, Gómez-Morales L, Lardé E, Denèfle T, Caballero-Hernández D, Merle-Béral H, Susin SA, Karoyan P, Martínez-Torres AC, and Rodríguez-Padilla C
- Subjects
- Animals, CD47 Antigen metabolism, Calcium metabolism, Cell Death drug effects, Cell Line, Tumor, Female, Humans, Kaplan-Meier Estimate, Leukemia, Experimental drug therapy, Leukemia, Experimental metabolism, Leukemia, Experimental pathology, Mice, Inbred BALB C, Peptides chemistry, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Thrombospondin 1 chemistry, Apoptosis drug effects, CD47 Antigen agonists, Membrane Potential, Mitochondrial drug effects, Peptides pharmacology
- Abstract
T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed thrombospondin-1-derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first-described serum-stable CD47-agonist peptide) on CEM and MOLT-4 human cell lines (T-ALL) and on one T-murine tumor lymphoblast cell-line (L5178Y-R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non-tumor cells after CD47 activation. In vivo, we determined that PKHB1-treatment in mice bearing the L5178Y-R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage-associated molecular patterns (DAMP) exposure (calreticulin, CRT) and release (ATP, heat shock proteins 70 and 90, high-mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining immunological memory. Our data indicate that PKHB1 induces caspase-independent and calcium-dependent cell death in leukemic cells while sparing non-tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Together, our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2019
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63. Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.
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Calippe B, Augustin S, Beguier F, Charles-Messance H, Poupel L, Conart JB, Hu SJ, Lavalette S, Fauvet A, Rayes J, Levy O, Raoul W, Fitting C, Denèfle T, Pickering MC, Harris C, Jorieux S, Sullivan PM, Sahel JA, Karoyan P, Sapieha P, Guillonneau X, Gautier EL, and Sennlaub F
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- Animals, Complement Factor H genetics, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immunohistochemistry, Inflammation genetics, Macular Degeneration genetics, Mice, Mice, Knockout, Peritonitis genetics, Peritonitis immunology, Polymorphism, Single Nucleotide, CD47 Antigen immunology, Complement Factor H immunology, Inflammation immunology, Macular Degeneration immunology
- Abstract
Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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64. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.
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Martinez-Torres AC, Quiney C, Attout T, Boullet H, Herbi L, Vela L, Barbier S, Chateau D, Chapiro E, Nguyen-Khac F, Davi F, Le Garff-Tavernier M, Moumné R, Sarfati M, Karoyan P, Merle-Béral H, Launay P, and Susin SA
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- Aged, Aged, 80 and over, Animals, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, Mice, Mice, Inbred NOD, Middle Aged, Peptides therapeutic use, Thrombospondin 1 therapeutic use, Apoptosis drug effects, B-Lymphocytes metabolism, CD47 Antigen metabolism, Drug Resistance, Neoplasm, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Peptides pharmacology, Phospholipase C gamma metabolism
- Abstract
Background: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides., Methods and Findings: In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease., Conclusions: Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.
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- 2015
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65. Synthesis and evaluation of analogues of N-phthaloyl-l-tryptophan (RG108) as inhibitors of DNA methyltransferase 1.
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Asgatay S, Champion C, Marloie G, Drujon T, Senamaud-Beaufort C, Ceccaldi A, Erdmann A, Rajavelu A, Schambel P, Jeltsch A, Lequin O, Karoyan P, Arimondo PB, and Guianvarc'h D
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- Catalytic Domain, Cell Line, Tumor, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases chemistry, Humans, Molecular Docking Simulation, Phthalic Acids chemical synthesis, Phthalic Acids chemistry, Phthalic Acids pharmacology, Phthalimides chemistry, Phthalimides pharmacology, Stereoisomerism, Structure-Activity Relationship, Tryptophan chemical synthesis, Tryptophan chemistry, Tryptophan pharmacology, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, Phthalimides chemical synthesis, Tryptophan analogs & derivatives
- Abstract
DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.
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- 2014
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66. 3-Substituted prolines: from synthesis to structural applications, from peptides to foldamers.
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Mothes C, Caumes C, Guez A, Boullet H, Gendrineau T, Darses S, Delsuc N, Moumné R, Oswald B, Lequin O, and Karoyan P
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- Proline analogs & derivatives, Protein Structure, Secondary, Peptides chemistry, Proline chemical synthesis, Proline chemistry
- Abstract
Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Despite the lack of hydrogen bonds and thanks to conformational restriction of flexibility linked to the pyrrolidine ring, proline is able to stabilize peptide secondary structures such as b-turns or polyproline helices. These unique conformational properties have aroused a great interest in the development of proline analogues. Among them, proline chimeras are tools combining the proline restriction of flexibility together with the information brought by natural amino acids side chains. This review will focus on the chemical syntheses of 3-substituted proline chimeras of potential use for peptide syntheses and as potential use as tools for SAR studies of biologically active peptides and the development of secondary structure mimetics. Their influence on peptide structure will be briefly described.
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- 2013
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67. β-Amino acids containing peptides and click-cyclized peptide as β-turn mimics: a comparative study with 'conventional' lactam- and disulfide-bridged hexapeptides.
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Larregola M, Lequin O, Karoyan P, Guianvarc'h D, and Lavielle S
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- Amino Acid Sequence, Cyclization, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Molecular Structure, Peptides chemical synthesis, Peptides genetics, Amino Acids chemistry, Disulfides chemistry, Lactams chemistry, Peptides chemistry, Protein Structure, Secondary
- Abstract
The increasing interest in click chemistry and its use to stabilize turn structures led us to compare the propensity for β-turn stabilization of different analogs designed as mimics of the β-turn structure found in tendamistat. The β-turn conformation of linear β-amino acid-containing peptides and triazole-cyclized analogs were compared to 'conventional' lactam- and disulfide-bridged hexapeptide analogs. Their 3D structures and their propensity to fold in β-turns in solution, and for those not structured in solution in the presence of α-amylase, were analyzed by NMR spectroscopy and by restrained molecular dynamics with energy minimization. The linear tetrapeptide Ac-Ser-Trp-Arg-Tyr-NH(2) and both the amide bond-cyclized, c[Pro-Ser-Trp-Arg-Tyr-D-Ala] and the disulfide-bridged, Ac-c[Cys-Ser-Trp-Arg-Tyr-Cys]-NH(2) hexapeptides adopt dominantly in solution a β-turn conformation closely related to the one observed in tendamistat. On the contrary, the β-amino acid-containing peptides such as Ac-(R)-β(3) -hSer-(S)-Trp-(S)-β(3) -hArg-(S)-β(3) -hTyr-NH(2) , and the triazole cyclic peptide, c[Lys-Ser-Trp-Arg-Tyr-βtA]-NH(2) , both specifically designed to mimic this β-turn, do not adopt stable structures in solution and do not show any characteristics of β-turn conformation. However, these unstructured peptides specifically interact in the active site of α-amylase, as shown by TrNOESY and saturation transfer difference NMR experiments performed in the presence of the enzyme, and are displaced by acarbose, a specific α-amylase inhibitor. Thus, in contrast to amide-cyclized or disulfide-bridged hexapeptides, β-amino acid-containing peptides and click-cyclized peptides may not be regarded as β-turn stabilizers, but can be considered as potential β-turn inducers., (Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.)
- Published
- 2011
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68. The combination of prolinoamino acids and cyclopropylamino acids leads to fully functionalized, stable β-turns in water.
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Guitot K, Larregola M, Pradhan TK, Vasse JL, Lavielle S, Bertus P, Szymoniak J, Lequin O, and Karoyan P
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- Crystallography, X-Ray, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Oligopeptides chemical synthesis, Stereoisomerism, Cyclopropanes chemistry, Oligopeptides chemistry, Proline chemistry, Water chemistry
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- 2011
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69. Radical stability directs electron capture and transfer dissociation of β-amino acids in peptides.
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Ben Hamidane H, Vorobyev A, Larregola M, Lukaszuk A, Tourwé D, Lavielle S, Karoyan P, and Tsybin YO
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- Electron Transport, Electrons, Molecular Structure, Stereoisomerism, Amino Acids chemistry, Mass Spectrometry methods, Peptides chemistry
- Abstract
We report on the characteristics of the radical-ion-driven dissociation of a diverse array of β-amino acids incorporated into α-peptides, as probed by tandem electron-capture and electron-transfer dissociation (ECD/ETD) mass spectrometry. The reported results demonstrate a stronger ECD/ETD dependence on the nature of the amino acid side chain for β-amino acids than for their α-form counterparts. In particular, only aromatic (e.g., β-Phe), and to a substantially lower extent, carbonyl-containing (e.g., β-Glu and β-Gln) amino acid side chains, lead to N-Cβ bond cleavage in the corresponding β-amino acids. We conclude that radical stabilization must be provided by the side chain to enable the radical-driven fragmentation from the nearby backbone carbonyl carbon to proceed. In contrast with the cleavage of backbones derived from α-amino acids, ECD of peptides composed mainly of β-amino acids reveals a shift in cleavage priority from the N-Cβ to the Cα-C bond. The incorporation of CH2 groups into the peptide backbone may thus drastically influence the backbone charge solvation preference. The characteristics of radical-driven β-amino acid dissociation described herein are of particular importance to methods development, applications in peptide sequencing, and peptide and protein modification (e.g., deamidation and isomerization) analysis in life science research., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2010
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70. Prolinoamino acids as tools to build bifunctionalized, stable beta-turns in water.
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Mothes C, Larregola M, Quancard J, Goasdoué N, Lavielle S, Chassaing G, Lequin O, and Karoyan P
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- Circular Dichroism, Magnetic Resonance Spectroscopy, Peptides chemistry, Protein Structure, Secondary, Proline chemistry, Water chemistry
- Published
- 2010
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71. Beta-homo-amino acid scan of angiotensin IV.
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Lukaszuk A, Demaegdt H, Szemenyei E, Tóth G, Tymecka D, Misicka A, Karoyan P, Vanderheyden P, Vauquelin G, and Tourwé D
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- Amino Acid Substitution, Aminopeptidases antagonists & inhibitors, Angiotensin II chemical synthesis, Angiotensin II chemistry, Angiotensin II pharmacology, Animals, Binding Sites, CD13 Antigens antagonists & inhibitors, CHO Cells, Cell Line, Cell Membrane drug effects, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Molecular Structure, Receptor, Angiotensin, Type 1 drug effects, Structure-Activity Relationship, Amino Acids chemistry, Angiotensin II analogs & derivatives, Enzyme Inhibitors chemical synthesis
- Abstract
Angiotensin IV, a metabolite of angiotensin II, inhibits the enzyme insulin regulated aminopeptidase or IRAP and also, although with lower potency, aminopeptidase-N (AP-N). When both beta (2)-homo amino acid- and beta (3)-homo amino acid substitutions were used, allowed the identification of H-( R)beta (2)hVal-Tyr-Ile-His-Pro-beta (3)hPhe-OH as a potent and stable Ang IV analog with high selectivity for IRAP versus AP-N and the AT1 receptor.
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- 2008
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72. High affinity Grb2-SH3 domain ligand incorporating Cbeta-substituted prolines in a Sos-derived decapeptide.
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Jacquot Y, Broutin I, Miclet E, Nicaise M, Lequin O, Goasdoué N, Joss C, Karoyan P, Desmadril M, Ducruix A, and Lavielle S
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- GRB2 Adaptor Protein metabolism, Humans, Ligands, Models, Molecular, Peptide Fragments metabolism, Proline metabolism, Protein Binding, Son of Sevenless Proteins metabolism, GRB2 Adaptor Protein chemistry, Peptide Fragments chemistry, Proline chemistry, Son of Sevenless Proteins chemistry, src Homology Domains
- Abstract
Peptide ligands that disrupt MAPK pathways are of great interest for a better understanding of these signalling cascades and represent therefore an attractive target to control cell degenerative processes. In that context, selective disruption of the upstream Grb2/Sos complex in the Ras/MAPK cascade has focused extensive work. The Sos PPII decapeptide, which interacts with the Grb2-SH3 domains, has been modified in various positions and the best inhibitors designed so far are either dimeric ligands or peptoid analogues of the VPPPVPPRRR sequence. We report the synthesis of new Grb2 ligands in which the key Val5 residue has been replaced by a cis C(beta)-substituted proline. Both fluorescence and ITC assays have been employed to measure the affinity of these substituted peptides for a recombinant Grb2 protein. Whereas proline in position 5 completely abolished the binding potency, a cis C(beta)-methyl-L-proline restored the affinity. Other cis C(beta)-proline substituents led to a complete loss of binding potency. Combining the best modifications: a cis C(beta)-methylproline 5, N-acetylation, C-carboxamide and dimerization yielded a 560-fold affinity enhancement compared to the wild-type VPPPVPPRRR sequence. This study shows that C(beta)-substituted prolines may constitute a new alternative for PPII ligands, combining entropy and enthalpy beneficial effects.
- Published
- 2007
- Full Text
- View/download PDF
73. Efficient synthesis of beta2-amino acid by homologation of alpha-amino acids involving the Reformatsky reaction and Mannich-type imminium electrophile.
- Author
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Moumne R, Lavielle S, and Karoyan P
- Subjects
- Amination, Bromine chemistry, Esters chemical synthesis, Esters chemistry, Fluoroacetates chemistry, Mannich Bases chemistry, Methylation, Molecular Structure, Stereoisomerism, Amino Acids chemical synthesis, Amino Acids chemistry, Electrons, Quaternary Ammonium Compounds chemistry
- Abstract
Development of new methods for the synthesis of beta-amino acids is important as polymers of these compounds are promising peptidomimetic candidates in medicinal chemistry. We report here our findings on a new and highly efficient general strategy for the synthesis of beta2-amino acids by homologation of alpha-amino acids, involving the Reformatsky reaction and Mannich-type imminium electrophile.
- Published
- 2006
- Full Text
- View/download PDF
74. Conformational analysis of the C-terminal Gly-Leu-Met-NH2 tripeptide of substance P bound to the NK-1 receptor.
- Author
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Sagan S, Quancard J, Lequin O, Karoyan P, Chassaing G, and Lavielle S
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Humans, Linear Models, Models, Molecular, Proline chemistry, Protein Binding, Protein Conformation, Peptide Fragments chemistry, Peptide Fragments metabolism, Receptors, Neurokinin-1 metabolism, Substance P chemistry, Substance P metabolism
- Abstract
We examined the effect of simultaneously incorporating proline or proline-amino acid chimeras in positions 9, 10, and/or 11 of substance P, on the affinity for the two NK-1 binding sites and on second-messenger activation. Because these 3-substituted prolines constrain not only the (phi,psi) values of the peptide backbone, but also the chi space of the amino acid side chain, we were able to gather data on the structural requirements for high-affinity binding to the NK-1 receptor. We were able to confirm that this C-terminal component is crucial and that it should adopt an extended conformation close to a polyproline II structure when bound to the receptor. The partial additivity of these constraints, more specifically, for the NK-1M site, suggests that the peptide backbone flexibility around the hinge-point residue Gly9 is essential to subtly position crucial side chains.
- Published
- 2005
- Full Text
- View/download PDF
75. Proton affinity of diastereoisomers of modified prolines using the kinetic method and density functional theory calculations: role of the cis/trans substituent on the endo/exo ring conformation.
- Author
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Mezzache S, Pepe C, Karoyan P, Fournier F, and Tabet JC
- Subjects
- Algorithms, Glutamic Acid analogs & derivatives, Glutamic Acid chemistry, Kinetics, Leucine analogs & derivatives, Leucine chemistry, Models, Molecular, Molecular Conformation, Stereoisomerism, Thermodynamics, Proline analogs & derivatives, Proline chemistry
- Abstract
The proton affinity (PA) of cis/trans-3-prolinoleucines and cis/trans-3-prolinoglutamic acids have been studied by the kinetic method and density functional theory (DFT) calculations. Several conformations of the neutral and the protonated modified prolines, in particular the endo and exo ring conformations, were analyzed with respect to their contribution to the PA values. When the substituent is an alkyl, both the diastereoisomers have the same PA value. However, the PA values for the diastereoisomers are different when the substituted chain contains functional groups (e.g. a carboxyl group). This variation in PA values could be attributed to the existence of intramolecular hydrogen bonds., (Copyright (c) 2005 John Wiley & Sons, Ltd.)
- Published
- 2005
- Full Text
- View/download PDF
76. Characterization of the bioactive conformation of the C-terminal tripeptide Gly-Leu-Met-NH2 of substance P using [3-prolinoleucine10]SP analogues.
- Author
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Quancard J, Karoyan P, Sagan S, Convert O, Lavielle S, Chassaing G, and Lequin O
- Subjects
- Animals, Binding Sites, CHO Cells, Cricetinae, Humans, Leucine metabolism, Models, Molecular, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments genetics, Protein Binding, Receptors, Neurokinin-1 metabolism, Substance P genetics, Leucine chemistry, Peptide Fragments chemistry, Peptide Fragments metabolism, Protein Conformation, Substance P chemistry, Substance P metabolism
- Abstract
Residue Leu10 of substance P (SP) is critical for NK-1 receptor recognition and agonist activity. In order to probe the bioactive conformation of this residue, cis- and trans-3-substituted prolinoleucines were introduced in position 10 of SP. The substituted SP analogues were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in CHO cells transfected with the human NK-1 receptor. [trans-3-prolinoleucine10]SP retained affinity and potency similar to SP whereas [cis-3-prolinoleucine10]SP shows dramatic loss of affinity and potency. To analyze the structural implications of these biological results, the conformational preferences of the SP analogues were analyzed by NMR spectroscopy and minimum-energy conformers of Ac-cis-3-prolinoleucine-NHMe, Ac-trans-3-prolinoleucine-NHMe and model dipeptides were generated by molecular mechanics calculations. From NMR and modeling studies it can be proposed that residue Leu10 of SP adopts a gauche(+) conformation around the chi1 angle and a trans conformation around the chi2 angle in the bioactive conformation. Together with previously published results, our data indicate that the C-terminal SP tripeptide should preferentially adopt an extended conformation or a PPII helical structure when bound to the receptor.
- Published
- 2003
- Full Text
- View/download PDF
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