Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Jean-Michel Longpré is active.

Publication


Featured researches published by Jean-Michel Longpré.


FEBS Letters | 2006

Inhibition of human matriptase by eglin c variants

Antoine Désilets; Jean-Michel Longpré; Marie-Eve Beaulieu; Richard Leduc

Based on the enzyme specificity of matriptase, a type II transmembrane serine protease (TTSP) overexpressed in epithelial tumors, we screened a cDNA library expressing variants of the protease inhibitor eglin c in order to identify potent matriptase inhibitors. The most potent of these, R1K4′‐eglin, which had the wild‐type Pro45 (P1 position) and Tyr49 (P4′ position) residues replaced with Arg and Lys, respectively, led to the production of a selective, high affinity (K i of 4 nM) and proteolytically stable inhibitor of matriptase. Screening for eglin c variants could yield specific, potent and stable inhibitors to matriptase and to other members of the TTSP family.


Journal of Clinical Investigation | 2014

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Michel Demeule; Nicolas Beaudet; Anthony Regina; Élie Besserer-Offroy; Alexandre Murza; Pascal Tétreault; Karine Belleville; Christian Che; Alain Larocque; Carine Thiot; Richard Béliveau; Jean-Michel Longpré; Eric Marsault; Richard Leduc; Jean E. Lachowicz; Steven L. Gonias; Jean-Paul Castaigne; Philippe Sarret

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.


Journal of Medicinal Chemistry | 2016

Discovery and Structure–Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

Alexandre Murza; Xavier Sainsily; David Coquerel; Jérôme Côté; Patricia Marx; Élie Besserer-Offroy; Jean-Michel Longpré; Jean Lainé; Bruno Reversade; Dany Salvail; Richard Leduc; Robert Dumaine; Olivier Lesur; Mannix Auger-Messier; Philippe Sarret; Eric Marsault

ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELAs structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.


FEBS Letters | 2002

Ectodomain shedding of furin: kinetics and role of the cysteine-rich region

Jean-Bernard Denault; Lyne Bissonnette; Jean-Michel Longpré; Gabriel Charest; Pierre Lavigne; Richard Leduc

Furin, a member of the subtilisin‐like pro‐protein convertase family, is a type I membrane protein that undergoes ectodomain shedding. Metabolic labeling of cells stably expressing furin demonstrated that the shed form of furin is detected after 30 min. Moreover, sequence analysis revealed that specific residues of the cysteine‐rich region of furin aligned with those of tumor necrosis factor receptor, which is also shed. Introduction within furins cysteine‐rich region of mutations that impair TNFR1 shedding also abolished furin shedding. Our results show that shedding of furin occurs rapidly and further suggest that specific cysteine residues may impart a conformation to the enzyme, thereby affecting its susceptibility to proteolysis.


Journal of Medicinal Chemistry | 2015

C-Terminal modifications of apelin-13 significantly change ligand binding, receptor signaling, and hypotensive action.

Alexandre Murza; Élie Besserer-Offroy; Jérôme Côté; Patrick Bérubé; Jean-Michel Longpré; Robert Dumaine; Olivier Lesur; Mannix Auger-Messier; Richard Leduc; Philippe Sarret; Eric Marsault

Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family. This system plays an important role in the regulation of blood pressure and cardiovascular functions. To better understand the role of its C-terminal Phe(13) residue on ligand binding, receptor signaling, and hypotension, we report a series of modified analogues in which Phe(13) was substituted by unnatural amino acids. These modifications delivered new compounds exhibiting higher affinity and potency to inhibit cAMP accumulation compared to apelin-13. In particular, analogues Bpa(13) or (α-Me)Phe(13) were 30-fold more potent to inhibit cAMP accumulation than apelin-13. Tyr(OBn)(13) substitution led to a 60-fold improvement in binding affinity and induced stronger and more sustained drop in blood pressure compared to apelin-13. Our study identified new potent analogues of apelin-13, which represent valuable probes to better understand its structure-function relationship.


Biopolymers | 2014

Stability and degradation patterns of chemically modified analogs of apelin-13 in plasma and cerebrospinal fluid

Alexandre Murza; Karine Belleville; Jean-Michel Longpré; Philippe Sarret; Eric Marsault

Apelin is the endogenous ligand of APJ, which belongs to the superfamily of G protein‐coupled receptors. In recent years, the apelin/APJ system has been detected in many tissues and emerges as a promising target for the treatment of various pathophysiological conditions. Pyr1‐apelin‐13 is the major isoform of apelin in human plasma; however its stability and proteolytic degradation pattern remain poorly understood. The aim of the present study was first to identify the cleavage sites of Pyr1‐apelin‐13 in mouse, rat and human plasma and rat cerebrospinal fluid, then to determine its stability to proteolytic degradation following intravenous administration in rats. Secondly, key residues were substituted by natural and unnatural amino acids in order to examine the impact on in vitro stability and degradation pattern. The kinetics of degradation revealed that the Leu5‐Ser6 peptide bond of Pyr1‐apelin‐13 is the first cleavage observed in plasma, independently of the species. Replacement of Phe13 by unnatural amino acids showed a 10‐fold increase in plasma stability although the hydrolysis of Pro12‐Phe13 bond, previously described as a site of cleavage by ACE‐2, was not observed. In vivo, this Pro12‐Phe13 bond was cleaved yet appears as a minor product compared to hydrolysis of the Pro10‐Met11 bond. This study pinpoints the most critical amino acids targeted by proteases and will be instrumental for the design of Pyr1‐apelin‐13 analogs possessing increased stability.


Biochemical Journal | 2004

Identification of furin pro-region determinants involved in folding and activation.

Lyne Bissonnette; Gabriel Charest; Jean-Michel Longpré; Pierre Lavigne; Richard Leduc

The pro-region of the subtilisin-like convertase furin acts early in the biosynthetic pathway as an intramolecular chaperone to enable proper folding of the zymogen, and later on as an inhibitor to constrain the activity of the enzyme until it reaches the trans -Golgi network. To identify residues that are important for pro-region function, we initially identified amino acids that are conserved among the pro-regions of various mammalian convertases. Site-directed mutagenesis of 17 selected amino acids within the 89-residue pro-region and biosynthetic labelling revealed that I60A-furin and H66A-furin were rapidly degraded in a proteasome-dependent manner, while W34A-furin and F67A-furin did not show any autocatalytic activation. Intriguingly, the latter mutants proteolytically cleaved pro-von Willebrand factor precursor to the mature polypeptide, suggesting that the mutations permitted proper folding, but did not allow the pro-region to exercise its role in inhibiting the enzyme. Homology modelling of furins pro-region revealed that residues Ile-60 and His-66 might be crucial in forming the binding interface with the catalytic domain, while residues Trp-34 and Phe-67 might be involved in maintaining a hydrophobic core within the pro-region itself. These results provide structural insights into the dual role of furins pro-region.


Journal of Medicinal Chemistry | 2014

Identification of 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid as a selective nonpeptide neurotensin receptor type 2 compound.

James B. Thomas; Angela M. Giddings; Robert W. Wiethe; Srinivas Olepu; Keith R. Warner; Philippe Sarret; Louis Gendron; Jean-Michel Longpré; Yanan Zhang; Scott P. Runyon; Brian P. Gilmour

Compounds active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects on different types of nociceptive modalities, including thermal, mechanical, and chemical stimuli. The NTS2 preferring peptide JMV-431 (2) and the NTS2 selective nonpeptide compound levocabastine (6) have been shown to be effective in relieving the pain associated with peripheral neuropathies. With the aim of identifying novel nonpeptide compounds selective for NTS2, we examined analogues of SR48692 (5a) using a FLIPR calcium assay in CHO cells stably expressing rat NTS2. This led to the discovery of the NTS2 selective nonpeptide compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid (NTRC-739, 7b) starting from the nonselective compound 5a.


Journal of Medicinal Chemistry | 2015

Synthesis and Characterization in Vitro and in Vivo of (l)-(Trimethylsilyl)alanine Containing Neurotensin Analogues

Roberto Fanelli; Élie Besserer-Offroy; Adeline René; Jérôme Côté; Pascal Tétreault; Jasmin Collerette-Tremblay; Jean-Michel Longpré; Richard Leduc; Jean Martinez; Philippe Sarret; Florine Cavelier

The silylated amino acid (l)-(trimethylsilyl)alanine (TMSAla) was incorporated at the C-terminal end of the minimal biologically active neurotensin (NT) fragment, leading to the synthesis of new hexapeptide NT[8-13] analogues. Here, we assessed the ability of these new silylated NT compounds to bind to NTS1 and NTS2 receptors, promote regulation of multiple signaling pathways, induce inhibition of the ileal smooth muscle contractions, and affect distinct physiological variables, including blood pressure and pain sensation. Among the C-terminal modified analogues, compound 6 (JMV2007) carrying a TMSAla residue in position 13 exhibits a higher affinity toward NT receptors than the NT native peptide. We also found that compound 6 is effective in reversing carbachol-induced contraction in the isolated strip preparation assay and at inducing a drop in blood pressure. Finally, compound 6 produces potent analgesia in experimental models of acute and persistent pain.


Journal of Medicinal Chemistry | 2014

Identification of N-[(5-{[(4-methylphenyl)sulfonyl]amino}-3-(trifluoroacetyl)-1H-indol-1-yl)acetyl]-l-leucine (NTRC-824), a neurotensin-like nonpeptide compound selective for the neurotensin receptor type 2.

James B. Thomas; Angela M. Giddings; Robert W. Wiethe; Srinivas Olepu; Keith R. Warner; Philippe Sarret; Louis Gendron; Jean-Michel Longpré; Yanan Zhang; Scott P. Runyon; Brian P. Gilmour

Compounds acting via the neurotensin receptor type 2 (NTS2) are known to be active in animal models of acute and chronic pain. To identify novel NTS2 selective analgesics, we searched for NTS2 selective nonpeptide compounds using a FLIPR assay and identified the title compound (NTRC-824, 5) that, to our knowledge, is the first nonpeptide that is selective for NTS2 versus NTS1 and behaves like the endogenous ligand neurotensin in the functional assay.

Collaboration


Dive into the Jean-Michel Longpré's collaboration.

Top Co-Authors

Avatar

Philippe Sarret

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar

Richard Leduc

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Eric Marsault

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar

Alexandre Murza

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar

Jérôme Côté

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Olivier Lesur

Université de Sherbrooke

View shared research outputs
Top Co-Authors

Avatar

Robert Dumaine

Université de Sherbrooke

View shared research outputs
Researchain Logo
Decentralizing Knowledge