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Meudal Hervé


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Ingénieur d’études

Groupe thématique : RMN des biomolécules

Publications

2016   Références trouvées : 1

Bailleul G., Kravtzoff A., Joulin-Giet A., Lecaille F., Labas V., Meudal H., Loth K., Teixeira-Gomes A.-P, Gilbert F B, Coquet L., Jouenne T., Brömme D., Schouler C., Landon C., Lalmanach G. and Lalmanach A.-C.  (2016)

The Unusual Resistance of Avian Defensin AvBD7 to Proteolytic Enzymes Preserves Its Antibacterial Activity.

PLoS ONE (2016) 11 (8) e0161573


2015   Références trouvées : 1

Oukhatar, F., Meudal, H., Landon, C., Logothetis, N. K., Platas-Iglesias, C., Angelovski, G., Tóth, É.  (2015)

Macrocyclic Gd(3+) Complexes with Pendant Crown Ethers Designed for Binding Zwitterionic Neurotransmitters

Chemistry - A European Journal (2015) 21 (31) 11226-11237 - doi : 10.1002/chem.201500542
A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1) s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.

A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1) s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.


2014   Références trouvées : 1

Herve, V., Meudal, H., Labas, V., Rehault-Godbert, S., Gautron, J., Berges, M., Guyot, N., Delmas, A.F., Nys, Y. and Landon, C.  (2014)

Three-dimensional NMR Structure of Hen Egg Gallin (Chicken Ovodefensin) Reveals a New Variation of the beta-Defensin Fold

Journal of Biological Chemistry (2014) 289 (10) 7211-7220 - doi : 10.1074/jbc.M113.507046
Gallin is a 41-residue protein, first identified as a minor component of hen egg white and found to be antimicrobial against Escherichia coli. Gallin may participate in the protection of the embryo during its development in the egg. Its sequence is related to antimicrobial beta-defensin peptides. In the present study, gallin was chemically synthesized 1) to further investigate its antimicrobial spectrum and 2) to solve its three-dimensional NMR structure and thus gain insight into structure-function relationships, a prerequisite to understanding its mode(s) of action. Antibacterial assays confirmed that gallin was active against Escherichia coli, but no additional antibacterial activity was observed against the other Gram-positive or Gram-negative bacteria tested. The three-dimensional structure of gallin, which is the first ovodefensin structure to have been solved to date, displays a new five-stranded arrangement. The gallin three-dimensional fold contains the three-stranded antiparallel beta-sheet and the disulfide bridge array typical of vertebrate beta-defensins. Gallin can therefore be unambiguously classified as a beta-defensin. However, an additional short two-stranded beta-sheet reveals that gallin and presumably the other ovodefensins form a new structural subfamily of beta-defensins. Moreover, gallin and the other ovodefensins calculated by homology modeling exhibit atypical hydrophobic surface properties, compared with the already known vertebrate beta-defensins. These specific structural features of gallin might be related to its restricted activity against E. coli and/or to other yet unknown functions. This work provides initial understanding of a critical sequence-structure-function relationship for the ovodefensin family.

Gallin is a 41-residue protein, first identified as a minor component of hen egg white and found to be antimicrobial against Escherichia coli. Gallin may participate in the protection of the embryo during its development in the egg. Its sequence is related to antimicrobial beta-defensin peptides. In the present study, gallin was chemically synthesized 1) to further investigate its antimicrobial spectrum and 2) to solve its three-dimensional NMR structure and thus gain insight into structure-function relationships, a prerequisite to understanding its mode(s) of action. Antibacterial assays confirmed that gallin was active against Escherichia coli, but no additional antibacterial activity was observed against the other Gram-positive or Gram-negative bacteria tested. The three-dimensional structure of gallin, which is the first ovodefensin structure to have been solved to date, displays a new five-stranded arrangement. The gallin three-dimensional fold contains the three-stranded antiparallel beta-sheet and the disulfide bridge array typical of vertebrate beta-defensins. Gallin can therefore be unambiguously classified as a beta-defensin. However, an additional short two-stranded beta-sheet reveals that gallin and presumably the other ovodefensins form a new structural subfamily of beta-defensins. Moreover, gallin and the other ovodefensins calculated by homology modeling exhibit atypical hydrophobic surface properties, compared with the already known vertebrate beta-defensins. These specific structural features of gallin might be related to its restricted activity against E. coli and/or to other yet unknown functions. This work provides initial understanding of a critical sequence-structure-function relationship for the ovodefensin family.


2012   Références trouvées : 2

Buré, C., Marceau, P., Meudal, H. and Delmas, A.F.  (2012)

Synthesis and analytical investigation of C-terminally modified peptide aldehydes and ketone : application to oxime ligation

Journal of Peptide Science 18 (3) 147-154
C-terminally modified peptides aldehyde (glycinal and alpha-oxo aldehyde peptides) and ketone (pyruvic acid-containing

peptide) were synthesised to get new insights into the mechanism of acido-catalysed oxime ligation. Their tetrahedral

hydrated forms were investigated in solution and in the gas phase, using NMR and in-source collision-induced dissociation mass

spectrometry, respectively, and the kinetics of the oximation reactions followed using analytical HPLC. The results obtained confirmed

that the first step of the oximation reaction was the limiting step for the pyruvic acid-containing peptides because of the

steric effect and of the carbon angular strain of the ketone. The second step is the determining step for the aldehyde peptides

because the basicity of the oxygen of the hydroxyl function of the tetrahedral form is greater for glycinal than for alpha-oxo

aldehyde. These data strongly suggest that the hydrated form of the aldehyde partner has to be considered when oxime

reactions are performed in aqueous buffer.

C-terminally modified peptides aldehyde (glycinal and alpha-oxo aldehyde peptides) and ketone (pyruvic acid-containing
peptide) were synthesised to get new insights into the mechanism of acido-catalysed oxime ligation. Their tetrahedral
hydrated forms were investigated in solution and in the gas phase, using NMR and in-source collision-induced dissociation mass
spectrometry, respectively, and the kinetics of the oximation reactions followed using analytical HPLC. The results obtained confirmed
that the first step of the oximation reaction was the limiting step for the pyruvic acid-containing peptides because of the
steric effect and of the carbon angular strain of the ketone. The second step is the determining step for the aldehyde peptides
because the basicity of the oxygen of the hydroxyl function of the tetrahedral form is greater for glycinal than for alpha-oxo
aldehyde. These data strongly suggest that the hydrated form of the aldehyde partner has to be considered when oxime
reactions are performed in aqueous buffer.

Derache, C., Meudal, H., Aucagne, V., Mark, K.J., Cadène, M., Delmas, A.F., Lalmanach, A.C. and Landon, C.  (2012)

Initial insights into the structure-activity relationships of avian defensins

Journal of Biological Chemistry 287 (10) 7746-7755
Numerous β-defensins have been identified in birds and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins (AvBDs), and the present work was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D- proteins clearly indicates that there is no chiral partner. Therefore the bacterial membrane is in all likelihood the primary target. Moreover, this work evidences that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural 3-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of avian β-defensin′s family was analyzed. Well conserved residues were highlighted and the potential strategic role of the lysine 31 residue of AvBD2 emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.

Numerous β-defensins have been identified in birds and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins (AvBDs), and the present work was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D- proteins clearly indicates that there is no chiral partner. Therefore the bacterial membrane is in all likelihood the primary target. Moreover, this work evidences that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural 3-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of avian β-defensin′s family was analyzed. Well conserved residues were highlighted and the potential strategic role of the lysine 31 residue of AvBD2 emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.


2010   Références trouvées : 2

Paquet, F., Loth, K., Meudal, H., Culard, F., Genest, D., & Lancelot, G.,  (2010)

Refined solution structure and backbone dynamics of the archaeal MC1 protein.

FEBS Journal - 277 (24) 5133-5145

Da Silva, P., Rahioui, I., Laugier, C., Jouvensal, L., Meudal, H., Chouabe, C., Delmas, A.F. & Gressent, F.  (2010)

Molecular requirements for the insecticidal activity of the plant peptide PA1b

J. Biol. Chem., 285, 32689-32694.


2009   Références trouvées : 2

Derache, C., Labas, V., Aucagne, V., Meudal, H., Landon, C., Delmas, A.F., Magallon, T. & Lalmanach, A.C.  (2009)

Primary Structure and Antibacterial Activity of Chicken Bone Marrow-Derived beta-Defensins.

Antimicrob. Agents Chemother. 53, 4647-4655.

Aubert, Y., Chassignol, M., Roig, V., Mbemba, G., Weiss, J., Meudal, H., Mouscadet, J.F. & Asseline, U.  (2009)

Synthesis and anti-HIV-1 integrase activity of modified dinucleotides.

Eur. J. Med. Chem. 44, 5029-5044.


2008   Références trouvées : 1

Chauvin, T ; Durand, P ; Bernier, M ; Meudal, H ; Doan, BT ; Noury, F ; Badet, B ; Beloeil, JC ; Tóth, E   (2008)

Detection of enzymatic activity by PARACEST MRI : a general approach to target a large variety of enzymes

Angew. Chem. Int. Edit. 47 (23) 4370 -4372


2006   Références trouvées : 4

Morellet, N ; Meudal, H ; Bouaziz, S ; Roques, BP  (2006)

Structure of the zinc finger domain encompassing residues 13-51 of the nucleocapsid protein from simian immunodeficiency virus

Biochemical Journal 393 725-732 Part 3
The NCps (nucleocapsid proteins) of HIV-1 (HIV type 1), HIV-2 and SIV (simian immunodeficiency virus) are small highly basic proteins, characterized by the presence of two CCHC ZF (zinc finger) domains. NCps, closely associated with the dimeric RNA genome in the core of the virus particle, were shown to promote the specific encapsidation of the viral RNA and are implicated in reverse transcription. Solution structure of the HIV-1 NCp7 and complexes of NCp7 with RNA or DNA showed the critical relationships between the structure and its various functions. HIV-1 and HIV-2 have resulted respectively from transmissions of SIV from chimpanzees and sooty mangabeys.

The NCps (nucleocapsid proteins) of HIV-1 (HIV type 1), HIV-2 and SIV (simian immunodeficiency virus) are small highly basic proteins, characterized by the presence of two CCHC ZF (zinc finger) domains. NCps, closely associated with the dimeric RNA genome in the core of the virus particle, were shown to promote the specific encapsidation of the viral RNA and are implicated in reverse transcription. Solution structure of the HIV-1 NCp7 and complexes of NCp7 with RNA or DNA showed the critical relationships between the structure and its various functions. HIV-1 and HIV-2 have resulted respectively from transmissions of SIV from chimpanzees and sooty mangabeys.

Landon, C ; Meudal, H ; Boulanger, N ; Bulet, P ; Vovelle, F  (2006)

Solution structures of stomoxyn and spinigerin, two insect antimicrobial peptides with an a-helical conformation

Biopolymers 81 (2) 92-103
Stomoxyn and spinigerin belong to the class of linear cysteine-free insect antimicrobial peptides that kill a range of microorganisms, parasites, and some viruses but without any lytic activity against mammalian erythrocytes. Stomoxyn is localized in the gut epithelium of the nonvector stable fly that is sympatric with the trypanosome vector tsetse fly. Spinigerin is stored and secreted by hemocytes from the fungus-growing termite.

Stomoxyn and spinigerin belong to the class of linear cysteine-free insect antimicrobial peptides that kill a range of microorganisms, parasites, and some viruses but without any lytic activity against mammalian erythrocytes. Stomoxyn is localized in the gut epithelium of the nonvector stable fly that is sympatric with the trypanosome vector tsetse fly. Spinigerin is stored and secreted by hemocytes from the fungus-growing termite.

Landon, C ; Meudal, H ; Boulanger, N ; Bulet, P ; Stocklin, R ; Vovelle, F  (2006)

Solution structures of stomoxyn and spinigerin, two antimicrobial peptides from insects

Understanding Biology Using Peptides, 19th American Peptide Symposium 289-290 - Editor(s) : Blondelle, SE

Bilbille, Y ; Paquet, F ; Meudal, H ; Giraud-Panis, MJ ; Lancelot, G  (2006)

NMR studies of telomeric nucleoprotein complexes involving the Myb-like domain of the human telomeric protein TRF2

Comptes Rendus Chimie 9 (3-4) 452-458
In order to study the binding of the Myb-like domain of the human telomeric protein TRF2 (Myb-TRF2) with different structural components of the t-loop model, we report NMR studies of the binding of Myb-TRF2 protein with two repeats human telomeric DNA under three conformations. Our results showed that Myb-TRF2 binds to the duplex and even to the quadruplex and the random coil G-rich strand. The solution structure of Myb-TRF2 reported here looks like Myb-TRF1 suggesting similar DNA binding mode. As a matter of fact, we have shown that its binding to the human telomeric duplex presents great similarities with this of Myb-TRF1.

In order to study the binding of the Myb-like domain of the human telomeric protein TRF2 (Myb-TRF2) with different structural components of the t-loop model, we report NMR studies of the binding of Myb-TRF2 protein with two repeats human telomeric DNA under three conformations. Our results showed that Myb-TRF2 binds to the duplex and even to the quadruplex and the random coil G-rich strand. The solution structure of Myb-TRF2 reported here looks like Myb-TRF1 suggesting similar DNA binding mode. As a matter of fact, we have shown that its binding to the human telomeric duplex presents great similarities with this of Myb-TRF1.


2003   Références trouvées : 2

Anne, C ; Blommaert, A ; Turcaud, S ; Martin, AS ; Meudal, H ; Roques, BP  (2003)

Thio-derived disulfides as potent inhibitors of botulinum neurotoxin type B : Implications for zinc interaction

Bioorganic & Medicinal Chemistry 11 (21) 4655-4660
Botulinum neurotoxin type B causes the inhibition of acetylcholine release at the neuromuscular junction resulting in a flaccid paralysis designated botulism. This occurs through the cleavage of synaptobrevin, an intracellular critical component of neurotransmitter exocytosis, by the zinc-metallopeptidase activity of the smallest subunit of the toxin. Blocking the proteolytic activity may present an attractive approach to treat botulism as to date there is no efficient specific drug therapy avalaible. We have therefore recently described a series of ß-amino-thiol derived pseudotripeptides able of inhibiting the toxin at low (10(-8) M) concentration. In this study, binding characteristics of the protein's active site are explored through various structural modifications of the thiol functionality which was supposed to be a key structural constituent for effective zinc-ion chelation. Surprisingly, sulfanyl-derivatives such as symmetric disulfides were shown to be better inhibitors than their thiol-counterparts, the most potent compound displaying a K-i value of 3.4 nM. (C) 2003 Elsevier Ltd. All rights reserved.

Botulinum neurotoxin type B causes the inhibition of acetylcholine release at the neuromuscular junction resulting in a flaccid paralysis designated botulism. This occurs through the cleavage of synaptobrevin, an intracellular critical component of neurotransmitter exocytosis, by the zinc-metallopeptidase activity of the smallest subunit of the toxin. Blocking the proteolytic activity may present an attractive approach to treat botulism as to date there is no efficient specific drug therapy avalaible. We have therefore recently described a series of ß-amino-thiol derived pseudotripeptides able of inhibiting the toxin at low (10(-8) M) concentration. In this study, binding characteristics of the protein’s active site are explored through various structural modifications of the thiol functionality which was supposed to be a key structural constituent for effective zinc-ion chelation. Surprisingly, sulfanyl-derivatives such as symmetric disulfides were shown to be better inhibitors than their thiol-counterparts, the most potent compound displaying a K-i value of 3.4 nM. (C) 2003 Elsevier Ltd. All rights reserved.

Anne, C ; Turcaud, S ; Quancard, J ; Teffo, F ; Meudal, H ; Fournie-Zaluski, MC ; Roques, BP  (2003)

Development of potent inhibitors of botulinum neurotoxin type B

Journal of Medicinal Chemistry 46 (22) 4648-4656
Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing antagonists of the action of these toxins. One way is to inhibit their catalytic activity. In this study, we report the design of such inhibitors directed toward BoNT/B. A study of the S-1 subsite specificity, using several ß-amino thiols, has shown that this subsite prefers a p-carboxybenzyl moiety. The specificity of the S-1' and S-2' subsites was studied using two libraries of pseudotripeptides containing the S-1 synthon derived from the best ß-amino thiol tested. Finally, a selection of various non natural amino acids for the recognition of the "prime" domain led to the most potent inhibitor of BoNT/B described to date with a K-i value of 20 nM.

Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing antagonists of the action of these toxins. One way is to inhibit their catalytic activity. In this study, we report the design of such inhibitors directed toward BoNT/B. A study of the S-1 subsite specificity, using several ß-amino thiols, has shown that this subsite prefers a p-carboxybenzyl moiety. The specificity of the S-1’ and S-2’ subsites was studied using two libraries of pseudotripeptides containing the S-1 synthon derived from the best ß-amino thiol tested. Finally, a selection of various non natural amino acids for the recognition of the "prime" domain led to the most potent inhibitor of BoNT/B described to date with a K-i value of 20 nM.


2002   Références trouvées : 1

Inguimbert, N ; Coric, P ; Poras, H ; Meudal, H ; Teffot, F ; Fournie-Zaluski, MC ; Roques, BP  (2002)

Toward an optimal joint recognition of the S-1 ’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP)

Journal of Medicinal Chemistry 45 (7) 1477-1486
The formation of vasoconstrictors (e.g., angiotensin II and endothelin) and the inactivation of vasodilators (e.g., bradykinin and atrial natriuretic) by membrane-bound zinc metallopeptidases are key mechanisms in the control of blood pressure and fluid homeostasis. The way in which these peptides modulate physiological functions has been intensively studied. With the aim to develop compounds that can jointly block the three metallopeptidases-neutral endopeptidase (NEP, neprilysin), angiotensin-converting enzyme (ACE), and endothelin-converting enzyme (ECE-1)-we studied the common structural specificity of the S-1' subsites of these peptidases.

The formation of vasoconstrictors (e.g., angiotensin II and endothelin) and the inactivation of vasodilators (e.g., bradykinin and atrial natriuretic) by membrane-bound zinc metallopeptidases are key mechanisms in the control of blood pressure and fluid homeostasis. The way in which these peptides modulate physiological functions has been intensively studied. With the aim to develop compounds that can jointly block the three metallopeptidases-neutral endopeptidase (NEP, neprilysin), angiotensin-converting enzyme (ACE), and endothelin-converting enzyme (ECE-1)-we studied the common structural specificity of the S-1’ subsites of these peptidases.


2000   Références trouvées : 2

Bellier, B ; Million, ME ; DaNascimento, S ; Meudal, H ; Kellou, S ; Maigret, B ; Garbay, C  (2000)

Replacement of glycine with dicarbonyl and related moieties in analogues of the C-terminal pentapeptide of cholecystokinin : CCK2 agonists displaying a novel binding mode

Journal of Medicinal Chemistry 43 (20) 3614-3623
Recent advances in the field of cholecystokinin have indicated the possible occurrence of multiple affinity states of the CCK2 receptor. Besides, numerous pharmacological experiments performed "in vitro" and "in vivo" support the eventuality of different pharmacological profiles associated to CCK2 ligands. Indeed, some agonists are essentially anxiogenic and uneffective in memory tests, whereas others are not anxiogenic and appear as able to reinforce memory. The reference compound for the latter profile is the CCK-8 analogue BC 264 (Boc-Tyr(SO3H)-gnle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2).

Recent advances in the field of cholecystokinin have indicated the possible occurrence of multiple affinity states of the CCK2 receptor. Besides, numerous pharmacological experiments performed "in vitro" and "in vivo" support the eventuality of different pharmacological profiles associated to CCK2 ligands. Indeed, some agonists are essentially anxiogenic and uneffective in memory tests, whereas others are not anxiogenic and appear as able to reinforce memory. The reference compound for the latter profile is the CCK-8 analogue BC 264 (Boc-Tyr(SO3H)-gnle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2).

Chen, HX ; Noble, F ; Mothe, A ; Meudal, H ; Coric, P ; Danascimento, S ; Roques, BP ; George, P ; Fournie-Zaluski, MC  (2000)

Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors : Synthesis, biological properties, and antinociceptive activities

Journal of Medicinal Chemistry 43 (7) 1398-1408
The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutral endopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides, enkephalins, represents an attractive physiological approach in the search for new analgesics devoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the general formula H3N+-CH(R-1)-P(O)(OH)-CH2-CH(R-2)-CONH-CH(R-3)-COO-, able to act as transition-state analogues and to fit the S-1, S-1', and S-2' subsites of both enzymes were designed. Selection of the R-1, R-2, and R-3 residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K-i values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventricular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previously described dual inhibitors.

The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutral endopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides, enkephalins, represents an attractive physiological approach in the search for new analgesics devoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the general formula H3N+-CH(R-1)-P(O)(OH)-CH2-CH(R-2)-CONH-CH(R-3)-COO-, able to act as transition-state analogues and to fit the S-1, S-1’, and S-2’ subsites of both enzymes were designed. Selection of the R-1, R-2, and R-3 residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K-i values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventricular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previously described dual inhibitors.


1999   Références trouvées : 3

Druillennec, S ; Meudal, H ; Roques, BP ; Fournie-Zaluski, MC  (1999)

Nucleomimetic strategy for the inhibition of HIV-1 nucleocapsid protein NCp7 activities

Bioorganic & Medicinal Chemistry Letters 9 (4) 627-632
We report the synthesis and biological properties of three modified dinucleotides T*G, G*T and T*T in winch the natural phosphodiester linkage has been replaced by a methylene carboxamide unit. They have been designed to act as nucleomimetics of a sequence recognized by the HIV-1 nucleocapsid protein NCp7 and to inhibit this interaction. (C) 1999 Elsevier Science Ltd. All rights reserved.

We report the synthesis and biological properties of three modified dinucleotides T*G, G*T and T*T in winch the natural phosphodiester linkage has been replaced by a methylene carboxamide unit. They have been designed to act as nucleomimetics of a sequence recognized by the HIV-1 nucleocapsid protein NCp7 and to inhibit this interaction. (C) 1999 Elsevier Science Ltd. All rights reserved.

Martin, L ; Cornille, F ; Turcaud, S ; Meudal, H ; Roques, BP ; Fournie-Zaluski, MC  (1999)

Metallopeptidase inhibitors of tetanus toxin : A combinatorial approach

Journal of Medicinal Chemistry 42 (3) 515-525
The bacterial protein tetanus toxin (TeNt), which belongs to the family of zinc endopeptidases, cleaves synaptobrevin, an essential synaptic protein component of the neurotransmitter exocytosis apparatus, at a single peptide bond (Gln(76)-Phe(77)). This protease activity is a particularly attractive target for designing potent and selective synthetic inhibitors as a possible drug therapy for tetanus. ß-Aminothiols mimicking Gln(76) of synaptobrevin have been previously shown to inhibit the tetanus neurotoxin enzymatic activity in the 35-250 mu M range. These compounds have now been modified to interact with S' subsites of the TeNt active site, with the aim of increasing their inhibitory potencies. Combinatorial libraries of pseudotripeptides, containing an ethylene sulfonamide or an m-sulfonamidophenyl moiety as the P-1 side chain and natural amino acids in P-1' and P-2' positions, were synthesized. The best inhibitory activity was observed with Tyr and His as P-1' and P-2' components, respectively. This led to new inhibitors of TeNt with K-i values in the 3-4 mu M range. These molecules are the most potent inhibitors of TeNt described so far.

The bacterial protein tetanus toxin (TeNt), which belongs to the family of zinc endopeptidases, cleaves synaptobrevin, an essential synaptic protein component of the neurotransmitter exocytosis apparatus, at a single peptide bond (Gln(76)-Phe(77)). This protease activity is a particularly attractive target for designing potent and selective synthetic inhibitors as a possible drug therapy for tetanus. ß-Aminothiols mimicking Gln(76) of synaptobrevin have been previously shown to inhibit the tetanus neurotoxin enzymatic activity in the 35-250 mu M range. These compounds have now been modified to interact with S’ subsites of the TeNt active site, with the aim of increasing their inhibitory potencies. Combinatorial libraries of pseudotripeptides, containing an ethylene sulfonamide or an m-sulfonamidophenyl moiety as the P-1 side chain and natural amino acids in P-1’ and P-2’ positions, were synthesized. The best inhibitory activity was observed with Tyr and His as P-1’ and P-2’ components, respectively. This led to new inhibitors of TeNt with K-i values in the 3-4 mu M range. These molecules are the most potent inhibitors of TeNt described so far.

David, C ; Bischoff, L ; Meudal, H ; Mothe, A ; De Mota, N ; DaNascimento, S ; Llorens-Cortes, C ; Fournie-Zaluski, MC ; Roques, BP  (1999)

Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme

Journal of Medicinal Chemistry 42 (25) 5197-5211
The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to sc its S-1, S-1', and S-2' subsites. This analysis confirmed that the S-1 subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S-1' subsite is hydrophobic whereas the S-2' subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H3N+CH(CH2CH2SO3-)CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K-i of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II- and cholecystokinin CCK8 in the central nervous system.

The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to sc its S-1, S-1’, and S-2’ subsites. This analysis confirmed that the S-1 subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S-1’ subsite is hydrophobic whereas the S-2’ subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H3N+CH(CH2CH2SO3-)CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K-i of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II- and cholecystokinin CCK8 in the central nervous system.


1998   Références trouvées : 1

Bellier, B ; Da Nascimento, S ; Meudal, H ; Gincel, E ; Roques, BP ; Garbay, C  (1998)

Novel constrained CCK-B dipeptoid antagonists derived from pipecolic acid

Bioorganic & Medicinal Chemistry Letters 8 (11) 1419-1424
A new series of 4-substituted pipecolic acid derivatives was prepared and incorporated into dipeptoids. The resulting products behave as moderately potent CCK-B antagonists but their constrained structure and its comparison with structurally related compounds yield valuable information about the conformational requirements for optimal recognition of the CCK-B receptor by antagonists. (C) 1998 Elsevier Science Ltd. All rights reserved.

A new series of 4-substituted pipecolic acid derivatives was prepared and incorporated into dipeptoids. The resulting products behave as moderately potent CCK-B antagonists but their constrained structure and its comparison with structurally related compounds yield valuable information about the conformational requirements for optimal recognition of the CCK-B receptor by antagonists. (C) 1998 Elsevier Science Ltd. All rights reserved.


1997   Références trouvées : 3

Bellier, B ; McCortTranchepain, I ; Ducos, B ; Danascimento, S ; Meudal, H ; Noble, F ; Garbay, C ; Roques, BP  (1997)

Synthesis and biological properties of new constrained CCK-B antagonists : Discrimination of two affinity states of the CCK-B receptor on transfected CHO cells

Journal of Medicinal Chemistry 40 (24) 3947-3956
To improve our knowledge of the bioactive conformation of CCK-B antagonists, we have developed a new series of constrained dipeptoids whose synthesis and biochemical properties are reported here. These compounds, of general structure N-a-[(2-adamantyloxy)carbonyl]-a-methyltryptophanyl-(4-X)-proline, were designed by introducing a cyclization in the structure of the previously described CCK-B/peptoid antagonist RB 210, N-[N-[(2-adamantyloxy)carbonyl]-DL-a-methyltryptophanyl]-N-(2-phenylethyl)glycine (Blommaert et al. J. Med. Chem. 1993, 36, 2868-2877), by means of a five-membered ring.

To improve our knowledge of the bioactive conformation of CCK-B antagonists, we have developed a new series of constrained dipeptoids whose synthesis and biochemical properties are reported here. These compounds, of general structure N-a-[(2-adamantyloxy)carbonyl]-a-methyltryptophanyl-(4-X)-proline, were designed by introducing a cyclization in the structure of the previously described CCK-B/peptoid antagonist RB 210, N-[N-[(2-adamantyloxy)carbonyl]-DL-a-methyltryptophanyl]-N-(2-phenylethyl)glycine (Blommaert et al. J. Med. Chem. 1993, 36, 2868-2877), by means of a five-membered ring.

David, C ; Bischoff, L ; Meudal, H ; Llorens-Cortes, C ; Roques, BP ; Fournie-Zaluski, MC  (1997)

Characterization and inhibition of aminopeptidase A by a-mercapto-ß-amino acyl dipeptides

Letters in Peptide Science 4 (4-6) 411-414
In order to study the physiological role of aminopeptidase A (APA), several cl-mercapto-B-amino acyl dipeptides were synthesized to obtain compounds having a high affinity for APA and a high selectivity versus aminopeptidase N (APN). Sulfonamide and carboxylate moieties which have been shown to be recognized by the S-1 subsite of the enzyme were introduced on the side chain of the a-mercapto-ß-amino acyl sub-unit, the latter being coupled to dipeptides optimized S'(1) and S'(2) subsites by means of combinatorial chemistry. Good affinities (16 nM) were obtained, the to interact with the S' selectivity factors being up to 160-fold versus APN.

In order to study the physiological role of aminopeptidase A (APA), several cl-mercapto-B-amino acyl dipeptides were synthesized to obtain compounds having a high affinity for APA and a high selectivity versus aminopeptidase N (APN). Sulfonamide and carboxylate moieties which have been shown to be recognized by the S-1 subsite of the enzyme were introduced on the side chain of the a-mercapto-ß-amino acyl sub-unit, the latter being coupled to dipeptides optimized S’(1) and S’(2) subsites by means of combinatorial chemistry. Good affinities (16 nM) were obtained, the to interact with the S’ selectivity factors being up to 160-fold versus APN.

Bischoff, L ; David, C ; Martin, L ; Meudal, H ; Roques, BP ; FournieZaluski, MC  (1997)

2,4-Dinitrophenyl 4-methoxybenzyl disulfide : A new efficient reagent for the electrophilic sulfenylation of ß-amino ester enolates

Journal of Organic Chemistry 62 (14) 4848-4850


1996   Références trouvées : 3

Liu, WQ ; Carreaux, F ; Meudal, H ; Roques, BP ; Garbay Jaureguiberry, C  (1996)

Synthesis of constrained 4-(phosphonomethyl)phenylalanine derivatives as hydrolytically stable analogs of O-phosphotyrosine.

Tetrahedron 52 (12) 4411-4422
In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include a-methyl, ß-methyl ß,ß-dimethyl substitutions, a,ß-cyclization of Pmp and methyl substitution on the phosphonomethyl group of Pmp.

In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include a-methyl, ß-methyl ß,ß-dimethyl substitutions, a,ß-cyclization of Pmp and methyl substitution on the phosphonomethyl group of Pmp.

Coric, P ; Turcaud, S ; Meudal, H ; Roques, BP ; Fournie Zaluski, MC  (1996)

Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors

Journal of Medicinal Chemistry 39 (6) 1210-1219
An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensin II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP). This is support-ed by recent results obtained with potent dual inhibitors of the two zinc metallopeptidases, such as RE 105, HSCH2CH(CH3)PhCONHCH(CH3)COOH (Fournie-Zaluski et rrl. Proc, Natl. Acad. Sci. U.S.A, 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the stilt and renin angiotensin system status.

An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensin II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP). This is support-ed by recent results obtained with potent dual inhibitors of the two zinc metallopeptidases, such as RE 105, HSCH2CH(CH3)PhCONHCH(CH3)COOH (Fournie-Zaluski et rrl. Proc, Natl. Acad. Sci. U.S.A, 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the stilt and renin angiotensin system status.

FournieZaluski, MC ; Coric, P ; Thery, V ; Gonzalez, W ; Meudal, H ; Turcaud, S ; Michel, JB ; Roques, BP  (1996)

Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action

Journal of Medicinal Chemistry 39 (13) 2594-2608
Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C. ; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1', and S-2' subsites of this enzyme, (ii) and to interact with the S-1' and S-2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P. ; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition.

Mercaptoacyl dipeptides, containing a glycine Linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C. ; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S-1, S-1’, and S-2’ subsites of this enzyme, (ii) and to interact with the S-1’ and S-2’ subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P. ; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decreasein ACE inhibition.


1993   Références trouvées : 1

Guis, C ; Bruetschy, L ; Meudal, H ; Roques, BP ; Gacel, GA  (1993)

Investigation of the structural parameters involved in the delsta-opioid selectivity of several families of familes opioid-peptides

International Journal of Peptide and Protein Research 41 (6) 576-586
Three series of highly d-opioid selective peptides are now available, and each family is used as template to investigate the structural parameters involved in d-receptor recognition and in the modulation of the selectivity of the parent peptide. The first series includes cyclic derivatives such as Tyr-D-Pen-Gly-Phe-D-Pen(DPDPE) and Tyr-D-Pen-Gly-Phe-Pen(DPLPE) ; the second are the synthetic linear constrained peptides [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(DSTBULET), Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu) (BUBU) and especially Tyr-D-CyS(StBu)-Gly-Phe-Leu-Thr(OtBu) (BUBUC)] and the last one the natural peptides [Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2(deltorphin or dermenkephalin)and Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2 ([D-Ala2] deltorphin 1)].

Three series of highly d-opioid selective peptides are now available, and each family is used as template to investigate the structural parameters involved in d-receptor recognition and in the modulation of the selectivity of the parent peptide. The first series includes cyclic derivatives such as Tyr-D-Pen-Gly-Phe-D-Pen(DPDPE) and Tyr-D-Pen-Gly-Phe-Pen(DPLPE) ; the second are the synthetic linear constrained peptides [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(DSTBULET), Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu) (BUBU) and especially Tyr-D-CyS(StBu)-Gly-Phe-Leu-Thr(OtBu) (BUBUC)] and the last one the natural peptides [Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2(deltorphin or dermenkephalin)and Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2 ([D-Ala2] deltorphin 1)].