Groupe Pharmacochimie
Publié le Monday 5 January 2009, mis à jour le Wednesday 9 June 2010, byPharmacochemistry - Proteomics Group
Team leader : Patricia MELNYK, PR2, Lille2 University
Patricia Melnyk graduated as an engineer in chemistry in 1989 from Ecole Nationale de Chimie de Paris. She received his Ph.D. degree in 1993 from the University of Paris VI. During the thesis she developed novel total synthesis of new indolic pentacycles as tyrosine hydroxylase inductors. She did post-doctoral training from 1993 to 1994 in Paris (ENSCP) in the group of Pr G. Jaouen in the field of bioorganometallic chemistry and from 1994 to 1996 in Lille in the group of Pr A. Tartar, in the field of combinatorial and parallel synthesis. She worked in Cerep biotech company as chemistry laboratory manager then Combinatorial Chemistry group leader. She’s working since 2002 as a chemistry professor in Lille 2 University (UL2) and created his own group in 2004. She is member of several scientific boards and of the CNU (Conseil National des Universités, section 39 and now 85). In 2007, she created with Dr André Delacourte a start-up company, AlzProtect.
Contact : patricia.melnyk ibl.fr
Phone : +33 3 20 87 12 19
Fax : +33 3 20 87 12 35
Scientific members of the laboratory
| Permanent Scientists | ||
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Patricia MELNYK | PR2, UL2 |
| AlzProtect Staff | ||
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Stéphane BURLET | Drug Discovery project manager |
| Safiyat AMINE | Tech AlzProtect / UL2 | |
| Post Doctoral | ||
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Thi Huu NGUYEN | IR, UL2 (ANR) |
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Nicolas LEFUR | IR, UL2 (ANR) |
| Engineers/Technicians | ||
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Marie-Ange FONTAINE | Tech, UL2 |
| Paul Emmanuel LARCHANCHE | Tech, UL2 | |
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Guillaume HOCHART | IE, UL2 (OSEO) |
| Graduate Students | ||
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| Undergraduate Students | ||
| Thomas BEGUIN | Master 1, UL2 |
The aim of our group is to design and synthesize candidate-drug in the field of neurodegenerative (Alzheimer’s disease), neurologic and parasitic (Malaria) diseases. We are combining structurally based rational design and parallel synthesis of focused libraries. During the last years, in accordance with the general axis of the unit, we have started a program based on the design of c-Met inhibitors and their vectorisation. In parallel, H. Drobecq conducts a plateform of mass spectrometry – biomolecules analysis. He is thus engaged in a lot of research projects with national and international collaborations and is co-author of the publications.
New antimalarial compounds (collaboration Pr P. Grellier, EA3335, MNHN, Paris)
Chloroquine (CQ) was a mainstream drug in the fight against Plasmodium falciparum, but its efficacy is eroded by the emergence of resistant parasites. We have developed compounds able to accumulate into the food vacuole of the parasite, inhibit the heme polymerisation more efficiently than CQ. These compounds showed better antimalarial properties in vitro and in some cases in vivo. In all series, 1,4-bis(3-aminopropyl)piperazine linker provided better activity upon CQ-resistant strain.
Several series of amodiaquine analogs, devoided of the 4’-phenol substituent, which seem responsible of the toxicity, were synthesized and brought a new light on the SAR of the 4-anilinoquinolines family. We also designed and analysed amodiaquine and amopyroquine analogs, bearing new functionalities in 4’-position : amine, alkyle and aryle groups thanks to a Suzuki reaction and obtained two potent compounds.
In parallel, we also explored other type of compounds, leading to the synthesis of the glyoxylhydrazone type library of 80 compounds and focused library of iron chelating acylhydrazones from salicylic aldehyde.
Sigma-1 ligands as neuroprotective agents (collaborations Dr T. Maurice, Inserm U710 Montpellier ; Pr C. Vaccher, EA4034 Lille ; Pr R. Bordet, EA1046 Lille)
Sigma-1 protein and its effectors, endogeneous agonists or antagonists, are implicated in physiological desadaptions leading to addiction. Previously we showed the affinity of 1,2,3,4-tetrahydroisoquinoline-hydantoine (Tic-hydantoïne) mixed structure for σ 1 receptors. We have continued this research program working on the synthesic methodologies, TicHyd structure or amino side-chain.
Nanomolar, selective and non toxic agonists have shown a high potential for cocaine weaning and are under development.
C-Met inhibitors as anticancer agents (collaborations Dr V. Fafeur, UMR8161, Lille)
In collaboration with other teams in IBL, our aim is to design and synthesize inhibitors of c-Met tyrosine kinase activity and vectorise them specifically to cancer cells thanks to lipid nanoparticules decorated with functionalised dextrans. Depending on their functionalised level, these polymers could selectively interact with protein with bearing heparin binding domain, such as c-Met and HGF/SF. This was demonstrated in the case of PDGF-BB growth factor, and confirmed in the lab using polysaccharide microarrays. A new and controlled method of dextran lipidation allowing the preparation of grafted nanoparticules was developed. In parallel, the design of intracellular inhibitors combined both pharmacomodulation of published c-Met inhibitors and chemoinformatic search for new pharmacophores.
Anti Alzheimer compounds (collaborations Dr A. Delacourte, Inserm U837 Lille ; AlzProtect ; Pr C. Vaccher and Pr P. Odou, EA4034 Lille)
Alzheimer’s disease (AD) is a frequent neurodegenerative disorder in the aged population, provoking the complete loss of cognitive functions and dementia. There is no cure and symptomatic treatments available have marginal effects on patients and on the evolution of the disease. APP protein is in the heart of AD. One of its metabolites, the neurotoxic Aβ peptide, aggregates to form amyloid plaques according to the amyloidogenic pathway. The other competing way, the neurotrophic pathway, prevents the formation of Aβ peptide and provides APP fragments with neurotrophic and important neurophysiological functions: sAPPalpha and AICD.
Their absence could stimulate Tau pathology, degenerating process frequently encountered during aging and leading to AD.
Results obtained by A. Delacourte et al. from a human brain library showed that sAPPalpha and AICD decreased during AD. In a same way, familial forms of AD rely more on AICD decrease than Aβ modifications. All recent publications underlign the importance of APP loss of function in AD.
We have started a program aiming on slowing the degradation of important APP fragments by the endosome-lysosome system. We take advantage of our expertise of antimalarial compounds and chloroquine analogs. This last compound accumulates into the acidic food vacuole of the parasite and inhibits heme polymerisation. A library of several hundred of compounds was available in the lab and was screened on a cellular test. Hits were optimized and a new family of compounds (named MSBD) was patented (WO 2006 051489). Most potent derivatives increase APP-CTF alpha and AICD fragment 10 times, leading to a parallel decrease in Aβ secretion of 80%.
Our lead compound crosses the BBB, shows no toxicity on mouse model, no cardio or geno- toxicity and provides an interesting ADME-Tox profile. This project is funding by an “Aide au Transfert” Oseo grant.
In a parallel way, we have explored structurally different compounds with potent pharmacophores and good theorical physicochemical properties. We have thus identified and developed a new family which is under patenting. This project is funding by an ANR grant.
AlzProtect, a start-up company, was created to develop these compounds through preclinical and clinical phases. Our company was laureate of the “Concours national d’aide à la création d’entreprises innovantes” in 2007.
PUBLICATIONS (since 2004)
«Design, synthesis and antimalarial activity of a glyoxylylhydrazone library »
Ryckebusch, A. ; Fruchart, J.-S.; Cattiaux, L.; Rousselot-Pailley, P.; Leroux, V. ; Melnyk, O. ; Grellier, P. ; Mouray, E.; Sergheraert, C. ; Melnyk, P.
Bioorg. Med. Chem. Lett. 2004, 14, 4439-4443.
«Optimized Synthesis of tetrahydroisoquinoline-Hydantoins»
Charton, J.; Cazenave Gassiot, A.; Melnyk, P.; Girault-Mizzi, S.; Sergheraert, C.
Tetrahedron Lett. 2004, 45, 7081-7085.
«Synthesis and antimalarial evaluation of non-quinoline 1,4-bis(3-aminopropyl)piperazine derivatives »
Ryckebusch, A. ; Déprez-Poulain, R.; Debreu-Fontaine, M.-A. ; Vandaele, R. ; Grellier, P. ; Sergheraert, C. ; Melnyk, P.
Fundamental and Clinical Pharmacology 2004, 18, 593-599.
« A New Proteomic Approach to Study the Heterogeneity of Amyloid Beta Species in Alzheimer’s Disease»
Gompel, M.; Drobecq, H.; Vanmechelen, E.; Buée, L.; Melnyk, P. ; Sergeant, N.; Delacourte, A.
Molecular and Cellular Proteomics 2005, S185.
« Design, synthesis and antimalarial evaluation of new N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine Derivatives »
Ryckebusch, A. ; Debreu-Fontaine, M.-A. ; Mouray, E.; Grellier, P. ; Sergheraert, C. ; Melnyk, P.
Bioorg. Med. Chem. Lett. 2005, 15, 297-302.
« Nouvelles molécules interagissant sur le métabolisme de l’APP »
Melnyk, P.; Sergeant, N.; Buée, L.; Delacourte, A.
Rev. Neurol.(France) 2005, 161 (12), 4S32.
«1,4-bis(3-aminopropyl)pipérazine libraries : from the discovery of classical chloroquine-like antimalarials to the identification of new targets »
Déprez-Poulain, R.; Melnyk, P.
Combinatorial Chemistry and High Throughput Screening 2005, 8(1), 39-48
«Synthesis and pharmacological evaluation of Tic-Hydantoin derivatives as selective σ1 ligands. Part 1»
Charton, J.; Cazenave Gassiot, A.; Girault-Mizzi, S.; Debreu-Fontaine, M.-A.; Melnyk, P.; Sergheraert, C.
Bioorg. Med. Chem. Lett. 2005, 15, 4833-4837.
«Synthesis and pharmacological evaluation of Tic-Hydantoin derivatives as selective σ1 ligands. Part 2»
Cazenave Gassiot, A.; Charton, J.; Girault-Mizzi, S.; Gilleron, P.; Debreu-Fontaine, M.-A.; Sergheraert, C. ; Melnyk, P.
Bioorg. Med. Chem. Lett. 2005, 15, 4828-4832.
«The proteome and secretome of human arterial smooth muscle cells »
Proteomics 2005, 5(2), 585-96.
«Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by gamma-secretase dependant mechanism »
Vingtdeux, V.; Hamdane, M.; Gompel, M. ; Begard, S. ; Drobecq, H. ; Ghestem, A. ; Grosjean, M.-E. ; Kostanjevecki, V. ; Grognet, P. ; Vanmechelen, E.; Buée, L.; Delacourte, A.; Sergeant, N.
Neurobiology of Disease 2005, 20, 625-637.
« Galectin-4 and sulphatides in apical membrane trafficking in enterocyte-like cells »
Delacour, D.; Gouyer, V.; Zanetta, J.P.; Drobecq, H.; Leteurtre, E.; Grard, G.; Moreau-Hannedouche, O.; Maes, E.; Pons, A.; André, S.; LeBivic, A.; Gabius, H.J.; Manninen, A.; Simons, K.; Huet, G.
J. Cell. Biol. 2005, 169 (3), 491-501.
«Expression and purification of recombinant vascular endothelialstatin »
Caetano, B. ; Drobecq, H. ; Soncin, F.
Protein Exp Purif 2006, 46(1), 136-142.
« Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies »
Deramecourt, V.; Bombois, S.; Maurage, C.. Ghestem, A. ; Drobecq, H. ; Vanmechelen, E. ; Lebert, F. ; Pasquier, F.; Delacourte, A.
J. Neuropathol. Exp. Neurol. 2006, 65(3), 278-288.
« Requirement for galectin-3 in apical protein sorting »
Delacour, D.; Cramm-Behrens, C.I.; Drobecq, H.; LeBivic, A.; Naim, H.Y.; Jacof, R.
Curr. Biol. 2006, 16(4), 408-414.
« Design, synthesis and in vitro antimalarial activity of an acylhydrazone library »
Melnyk, P.; Leroux, V. ; Grellier, P. ; Sergheraert, C
Bioorg. Med. Chem. Lett 2006, 16, 31-35.
« Probing the role of the covalent linkage of ferrocene into a chloroquine template»
Biot, C. ; Daher, W.; Jarry, C.; Ndiaye, E.H.C.M.; Pelinski, L.; Khalife, J.; Fraisse, L.; Brocard, J.; Melnyk, P.; Forfar Bares, I.; Dive, D.
J. Med. Chem. 2006, 49, 4707-4714.
« Similar Structure Activity Relationships of Quinoline Derivatives for antiprion and antimalarial effects»
Klingenstein, R.; Melnyk, P.; Leliveld, R. S. ; Ryckebusch, A.; Korth, C.
J. Med. Chem. 2006, 49, 5300-5308.
« Design and Synthesis of new Met kinase inhibitors»
Barras, A. ; Dupont, N. ; Horvath, D.; Melnyk, P.
Fundamental and Clinical Pharmacology 2006, 20, 621.
« Synthesis and Evaluation of Tetrahydroquinoline-Hydantoine Derivatives as σ1 Receptor Selective Ligands»
Toussaint, M. ; Cazenave Gassiot, A.; Charton, J.; Melnyk, P.
Fundamental and Clinical Pharmacology 2006, 20, 626.
« Design, Synthesis and Antimalarial activity of some new Amodiaquine and Amopyroquine analogues»
Paunescu, E.; Susplugas, S.; Mouray, E.; Grellier, P.; Melnyk, P.
Fundamental and Clinical Pharmacology 2006, 20, 625.
« Proteomics unveil corticoid-induced S100A11 shuttling in keratinocyte differentiation »
Dezitter, X.; Hammoudi, F.; Belverge, N.; Deloulme, J.C.; Drobecq, H.; Masselot, B.; Formstecher, P.; Mendy, D.; Idziorek, T.
Biochem. Biophys. Res. Commun. 2007, 360 (3), 627-32.
« Alkalizing drugs induce accumulation of Amyloid Precursor Protein byproducts in luminal vesicles of multivesicular bodies»
Vingtdeux, V.; Hamdane, M.; Loyens, A. ; Gelé, P.; Drobecq, H. ; Begard, S. ; Galas, M.-C. ; Delacourte, A.; Beauvillain, J.-C.; Buée, L.; Sergeant, N.
J. Biol. Chem. 2007, 282, 18197-205.
« Mycobacterium smegmatis produces an HBHA homologue which is not involved in epithelial adherence »
Biet, F. ; Angela de Melo Marques, M. ; Grayon, M.; Xavier da Silveira, E.K.; Brennan, P.J.; Drobecq, H.; Raze, D.; Vidal Pessolani, M.C.; Locht, C.; Menozzi, F.D.
Microbes Infect. 2007, 9 (2), 175-82..
« Suzuki coupling reaction as the key step for the synthesis of 4’-substituted analogues of Amodiaquine»
Paunescu, E.; Matuszak, N.; Melnyk, P.
Tetrahedron 2007, 63, 12791-12810.
« Enzymatic methylation of the Mycobacterium tuberculosis heparin-binding haemagglutinin»
Host, H.; Drobecq, H.; Locht, C.; Menozzi, F.
FEMS Microbiol Lett. 2007, 268 (2), 144-50.
« Protein Kinase CK2 phosphorylation of EB2 regulates its function in the production of EBV infectious viral particles »
Medina-Palazon, C.; Gruffat, H.; Mure, F.; Filhol, O.; Vingtdeux-Didier, V.; Drobecq, H.; Cochet, C.; Sergeant, N.; Sergeant, A.; Manet, E.
J. Virol. 2007, 81 (21), 11850-60.
« The Peptidyl-Prolyl Isomerase and Chaperone Par27 of Bordetella pertussis as the Prototype for a New Group of Parvulins »
J. Mol. Biol. 2008, 376 (2), 414-426.
«Predicting left ventricular remodelling after a first myocardial infarction by plasma proteome analysis»
Pinet, F.; Beseme, O.; Cieniewki-Bernard, C.; Drobecq, H.; Jourdain, S. ; Lamblin, N. ; Amouyel, P. ; Bauters, C.
Proteomics 2008, 8 (9), 1798-1808.
« The CD81 partner EWI-2wint inhibits hepatitis C virus entry »
Rocha-Perugini, V.; Montpellier, C.; Delgrange, D.; Wychowski, C.; Helle, F.; Pillez, A.; Drobecq, H.; Le Naour, F. ; Charrin, S. ; Levy, S. ; Rubinstein, E. ; Dubuisson, J. ; Cocquerel, L.
PLoS ONE 2008, 3 (4), e1866.
« Synthesis and Antimalarial Activity of New Analogues of Amodiaquine»
Delarue-Cochin, S.; Paunescu, E.; Maes, L.; Mouray, E.; Sergheraert, C.; Grellier, P.; Melnyk, P.
Eur. J. Med. Chem. 2008, 43, 252-260.
« Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine and Amopyroquine»
Paunescu, E.; Susplugas, S.; Boll, E.; Vargas, R.A.; Mouray, E.; Grellier, P.; Melnyk, P.
Med. Chem. 2008, 4 (5), 407-425.
« Minimal chemical modification of reductive end of dextran to produce an amphiphilic polysaccharide able to incorporate onto lipid nanocapsules»
Richard, A.; Barras, A.; Ben Younes, A. Dupont, N.; Melnyk, P.
Bioconjugate Chem. 2008, 19 (7), 1491-1495.
« Neuroprotective and antidepressant-like effects of LC 03/55, a novel sigma-1 receptor ligand»
Venna, V.R.; Deplancke, D.; Melnyk, P.; Bordet, R.
Fundamental and Clinical Pharmacology 2008, 22, 1.
« Application of Saturation Dye 2D-DIGE Proteomics to characterize proteins modulated by oxidised low density lipoprotein treatment of human macrophages»
Dupont, A.; Chwastyniak, M.; Beseme, O.; Guihot, A.L.; Drobecq, H.; Amouyel, P. ; Pinet, F.
J. Proteome. Res. 2008, in press.
« Antioxidative effect of Bacteroides thetaiotaomicron extracts : superoxide dismutase identification »
Hochart-Behra, A.C. ; Behra-Millet, J. ; Sam, J. ; Drobecq, H.; Gressier, B. ; Luyckx, M.; Dine, T.; Brunet, C. ; Dubreuil, L.
Anal. Bioanal. Chem. 2008, in press.
« Autocrine induction of invasion and metastasis by tumor-assisted trypsin inhibitor in human colon cancer cells »
Gouyer, V. ; Fontaine, D. ; Dumont, P. ; de Wever, O. ; Fontayne-Devaud, H. ; Leteurtre, E. ; Truant, S. ; Delacour, D. ; Drobecq, H.; Kerckaert, J.P. ; deLaunoit, Y. ; Bracke, M.; Gespach, C.; Desseyn, J.L.; Huet, G.
Oncogene 2008, in press.
« Synthesis and Antimalarial Activity of Carbamate and Amide Derivatives of 4-anilinoquinoline»
Delarue-Cochin, S.; Grellier, P.; Maes, L.; Mouray, E.; Sergheraert, C.; Melnyk, P.
Eur. J. Med. Chem. 2008, in press, DOI : 10.1016/j.ejmech.2007.11.003
PATENTS
« Use of 1,4-bis(3-aminopropyl)piperazine derivatives in therapy »
Melnyk, P.; Sergeant, N.; Buée, L.; Delacourte, A.
Brevet européen déposé le 10 nov 2004 sous le n° 04 292674.1
« Use of 1,4-bis(3-aminoalkyl)piperazine derivatives in therapy »
Melnyk, P.; Sergeant, N.; Buée, L.; Delacourte, A.
Extension internationale WO 2006 051489
