Prolinoamino acides substitués en position 3 (synthèses, applications structurales et pharmacologiques dans le développement d'inhibiteurs d'interactions peptide-protéine et protéine-protéine)

Les interactions peptide-protéine et protéine-protéine sont au cœur de nombreux processus biologiques vitaux. L utilisation d acides aminés contraints est une stratégie efficace pour étudier et moduler ces interactions biologiques. Les acides aminés étudiés dans ce travail sont des prolines substituées en position 3 par les chaînes latérales des acides aminés naturels : les 3-prolinoamino acides. Une voie de synthèse générale développée au laboratoire est basée sur une réaction de carbocyclisation amino-zinca-ène-énolate. Lors de ce travail, la méthode a été étendue à la synthèse des cis-3-prolinohomotryptophanes. Une deuxième approche a été développée pour l obtention des 3-prolinoamino acides : des additions 1-4 permettent de fonctionnaliser le cycle pyrrolidine conduisant à la synthèse de la N-Boc-trans-3-prolinophénylalanine de manière diastéréosélective. L introduction de ces 3-prolinoamino acides dans une séquence hétérochirale de type D-Pro-NMeaa a permis d induire une structuration en coude b stable dans l eau, tout en conservant les fonctionnalités en position i+1 et i+2 du coude. Ces outils ont ensuite été utilisés pour construire des mimes de coudes b ciblant une interaction peptide-protéine telle que la somatostatine avec ses récepteurs, et une interaction protéine-protéine, l interaction entre Grb2 et le récepteur RTK. Enfin, les 3-prolinoamino acides sont utilisés dans le développement d inhibiteurs potentiels de l interaction Smac-XIAP.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers †

molecule

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

International audienceAbstract Purpose Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [ 18 F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [ 18 F]FDG. Methods Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [ 18 F]FDG and [ 18 F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. Results We demonstrate that mean lung density on CT as well as [ 18 F]FDG and [ 18 F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [ 18 F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [ 18 F]FDG and [ 18 F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [ 18 F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. Conclusion [ 18 F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy

First identification, geochemical characterization, and land-sea correlations of Holocene marine distal tephra from the Ecuadorian arc

International audienceCorrelations between marine distal ash layers and continental proximal volcanic deposits constitute a strong tool to investigate the eruptive chronology of an active volcanic arc, to constrain the detailed stratigraphy of the marine sediments, as well as help constraining the magnitude of some large explosive eruptions.In the Andean Northern Volcanic Zone (NVZ), Ecuadorian Holocene major explosive eruptions have been widely documented over the past 30 years, and a large geochemical and geochronological database is available. However, the dispersion of distal volcanic products associated with these events is poorly known, and investigation of offshore tephra fallout deposits appears essential to clarify the recurrence, magnitude, and impact of past major explosive eruptions, and thus better define the volcanic hazards.We present for the first time chemical and morphological features of 30 Holocene tephra layers sampled in marine cores off the Ecuadorian coast during the Amadeus and Atacames cruises. Tephra layers are mainly composed of glass shards visible to the naked eye (~50-150 µm) with some calcareous nannofossils, foraminifera and diatoms. We present new geochemical data obtained on these tephra layers and compare different analysis techniques applied on such material. Major and trace element contents were measured on single glass shards by electron microprobe and LA-ICP-MS (Laser Ablation Inductively Coupled Plasma Mass Spectrometry), respectively, and compared to bulk whole-rock measurements performed by ICP-AES (Atomic Emission Spectrometry). Pb isotopic composition was analyzed by MC-ICP-MS (MultiCollector ICP-MS). Comparison of the chemical and isotopic signature of marine tephra with data acquired on land allows us to correlate some historic events, but also highlights eruptions that do not seem to have been described otherwise.Finally, land-sea correlations of tephra fallout deposits will also provide temporal constraints to marine seismic records, constrain the age of the tectonic structures of the basin, and possibly better define the recurrence of paleoearthquakes in this region where the seismic hazard is particularly high

Study of marine sedimentary deposits along Ecuador and southern Colombia through land-sea correlations of volcanic ash: a powerful tool to improve dating of past major earthquakes

Along active margins, large magnitude earthquakes induce submarine slope instabilities, generating turbidite deposits and debris flows. These catastrophic events are recorded in the stratigraphy from the slope basins to the subduction trench. These sedimentary records provide a unique opportunity to time-extend local seismic catalogs, and their analysis is a strong tool to study the age, source and frequency of large past earthquakes. However, one of the main challenges is accurately dating the deposits, especially in settings where few datable foraminifers are available (below the Carbonate Compensation Depths, in low primary productivity environments, within sequences with poorly preserved hemipelagic sediments between erosive turbidites, etc…). In such cases, volcanic ash emitted during the largest eruptions represent robust stratigraphic markers distributed over thousands of square kilometers, which can provide valuable temporal constraints.Marine sediment cores collected during the Amadeus and Atacames oceanographic cruises (R/V L’Atalante; Collot et al., 2005; Michaud et al., 2015) reveal numerous turbidite deposits, which could be a consequence of earthquakes that occurred along the Ecuadorian margin during the Holocene. The knowledge of such events is essential to better assess the present and future seismic hazards, as well as their potentially destructive impact on marine and coastal environments. Silty to sandy turbidite layers are encountered at the mouth of the Esmeraldas and Patia Canyons, in northern Ecuador, whereas fine-grained turbidites are present at the Ecuadorian trench and in slope basins between Punta Galera and the Gulf of Guayaquil. Turbidite sequences are interbedded with volcanic ash and hemipelagic layers. In this study, we provide new 14C ages performed on planktonic foraminifera present in hemipelagic layers to constrain the age of turbidite sequences. We also characterized the lithofacies and geochemistry of distal volcanic ash fallouts, and we propose a first land-sea correlation of these deposits to identify their source. We show that products from at least eight explosive eruptions of Guagua Pichincha, Atacazo-Ninahuilca, Cotopaxi, and Cerro Machín volcanoes occurring between ~1.0 and 8.6 Ma are recorded in marine sediments. Correlation of ash layers between marine sedimentary cores allows us to provide time constraints to cores that contains turbidite sequences but cannot be dated using the radiocarbon method. Our multidisciplinary approach is innovative in this region and aims to be developed both offshore and onland to participate to a better evaluation of seismic and volcanic hazards in Ecuador

Study of marine sedimentary deposits along Ecuador and southern Colombia through land-sea correlations of volcanic ash: a powerful tool to improve dating of past major earthquakes

Along active margins, large magnitude earthquakes induce submarine slope instabilities, generating turbidite deposits and debris flows. These catastrophic events are recorded in the stratigraphy from the slope basins to the subduction trench. These sedimentary records provide a unique opportunity to time-extend local seismic catalogs, and their analysis is a strong tool to study the age, source and frequency of large past earthquakes. However, one of the main challenges is accurately dating the deposits, especially in settings where few datable foraminifers are available (below the Carbonate Compensation Depths, in low primary productivity environments, within sequences with poorly preserved hemipelagic sediments between erosive turbidites, etc…). In such cases, volcanic ash emitted during the largest eruptions represent robust stratigraphic markers distributed over thousands of square kilometers, which can provide valuable temporal constraints.Marine sediment cores collected during the Amadeus and Atacames oceanographic cruises (R/V L’Atalante; Collot et al., 2005; Michaud et al., 2015) reveal numerous turbidite deposits, which could be a consequence of earthquakes that occurred along the Ecuadorian margin during the Holocene. The knowledge of such events is essential to better assess the present and future seismic hazards, as well as their potentially destructive impact on marine and coastal environments. Silty to sandy turbidite layers are encountered at the mouth of the Esmeraldas and Patia Canyons, in northern Ecuador, whereas fine-grained turbidites are present at the Ecuadorian trench and in slope basins between Punta Galera and the Gulf of Guayaquil. Turbidite sequences are interbedded with volcanic ash and hemipelagic layers. In this study, we provide new 14C ages performed on planktonic foraminifera present in hemipelagic layers to constrain the age of turbidite sequences. We also characterized the lithofacies and geochemistry of distal volcanic ash fallouts, and we propose a first land-sea correlation of these deposits to identify their source. We show that products from at least eight explosive eruptions of Guagua Pichincha, Atacazo-Ninahuilca, Cotopaxi, and Cerro Machín volcanoes occurring between ~1.0 and 8.6 Ma are recorded in marine sediments. Correlation of ash layers between marine sedimentary cores allows us to provide time constraints to cores that contains turbidite sequences but cannot be dated using the radiocarbon method. Our multidisciplinary approach is innovative in this region and aims to be developed both offshore and onland to participate to a better evaluation of seismic and volcanic hazards in Ecuador

Marine tephra offshore Ecuador and Southern Colombia: first trench-to-arc correlations and implication for the magnitude of major eruptions

International audienceMajor eruptions in the Andes are mainly characterized by the emission of large volumes of gas and volcanic ash. The plume may reach the stratosphere and be transported by winds. In Ecuador, the prevailing winds are westward, and the volcanic ash, also called tephra, is transported towards the Pacific Ocean. Vallejo (2011) studied tephra layers present in marine terraces and proposed a first draft of the identification of their source in the Cordillera. However tephras deposited onshore may have been remobilized, eroded or covered by younger deposits. There are therefore several interests in studying tephras recorded in marine sediments : it allows to (1) know the age and source of major eruptions whose products reached the coast, (2) know the distribution of fallout from each major eruption, (3) estimate the volume of largest events, (4) participate to better assess the current volcanic hazard, and (5) provide temporal constraints on continental or marine sediments that cannot be dated by radiocarbon. To study the tephra layers recorded in marine sediments I have described the glass morphology and the mineralogy of tephra beds. To determine the source of the eruptions, I have used data published onshore (e.g., Hidalgo et al., 2008; Hall et Mothes, 2008; Robin et al., 2010). As each volcano has its own geochemical signature when we combine major, trace and isotope data, I compared them with geochemical analyses performed on distal tephra recorded in marine sediments. To determine the age of distal tephra beds, we have performed 14C ages on foraminifera present above and below the bed for tephra emitted during the past 50 ka, and d18O and biostratigraphy for the older deposits. In this presentation, I first presented our results obtained on cores collected during Amadeus (2005) and Atacames (2012) oceanic campaigns along the Ecuadorian margin, and recently published (Bablon et al., 2022). We have sampled 28 tephra layers, from coring sites that cover 5 degrees of latitude, from the southern half of Ecuador to southern Colombia. We observed four main lithofacies: isolated lenses that typical of bioturbation, layers with sharp and sometimes diffuse contacts in the upper part that correspond to primary deposits of tephra fallout, and successions of thin laminated layers that correspond to tephra layers reworked by turbidity currents, and that have not been sampled. Volcanic glass shards have various morphologies depending on the density of vesicles and their deformation, such as block-shaped glass without bubbles, pumice-shaped glass, or glass with completely elongated bubbles. The glass morphology of each tephra allows us to propose a first correlation of layers between each marine core. Concerning the geochemistry, glasses are mostly rhyolitic and belong to the low potassic series typical of the volcanic front, and to high potassic series typical of the eastern cordillera. This distinction between the eastern and western cordillera is also found in their trace element signature. To identify the source volcano, we used Sr and Pb isotopes. On The compositional fields of the volcanoes products overlap little and thus allows us to refine the correlations. We show that distal marine tephra come from the Cerro Machin in Colombia, and from Pichincha, Atacazo, and Cotopaxi volcanoes in Ecuador. Together with the determination of the sources, the radiocarbon dating of sediments allowed us to show that the oldest tephras belonged to the about 8 ka eruption of Cotopaxi, and the youngest correspond to the 10th century eruption of Pichincha. Using the spatial distribution of tephra, we made isopach maps of the fourth major eruptions of Pichincha, Atacazo and Cotopaxi, and we estimated their volumes. They vary between 1.3 and 6 km3, which corresponds to volcanic explosivity indexes of 5, thus eruptions which would be particularly destructive today. A perspective for our work is to study of turbidite beds present in the Holocene cores along the coast. As such deposits are emplaced during major earthquakes, and we can therefore use their correlation to identify past seiscally active areas.Unfortunately, some major Holocene eruptions described in the Cordillera and constitute stratigraphic markers have not been recorded in marine sediments. Tephra layers may have been destructed during drilling such as the very young 700 BP eruption of Quilotoa, they may have been dispersed by ocean currents, or tephra were not present in the cores du to a restricted distribution of deposits, for example for the 3000 BP eruption of Cuicocha (Vallejo, 2011).In the second part of my presentation, I focused on another case study, performed at ODP site 1239, above the Carnegie Ridge. This core is much deeper as it reaches 500 m, and sediments deposited about 10 Myr ago. It contains 24 tephra layers, and we focused on the thickest, 18 cm-thick at 7 m deep (Schipboard Scientific Party, 2003; Bablon et al., 2020). The main volcanic structure that could be the source of such a thick deposit is the Chalupas caldera, located in the Eastern Cordillera, near Cotopaxi volcano. About 50 km southwest of the caldera, we sampled the ignimbrite and dated the glass shards at 216 +/- 5 ka using the K-Ar dating method applied on glass shards. In order to verify if the ignimbrite and marine tephra of ODP Site 1239 belong to the same eruption, we have compared their geochemistry, and we have shown that their major and trace element contents are very close. To check the reliability of this land-sea correlation, we have also compared their ages. Variations of d18O are related to climate changes linked to the Earth's orbital forcing. We then used d18O data available to know the age of sediments as a function of depth. The stratigraphic position of the tephra layer corresponds to the 7d isotopic stage that occured at 220 ka, in agreement with our K-Ar age obtained onland. We then have shown that the 216 +/- 5 ka eruption of Chalupas is the largest of the Quaternary in northern Andes, with products that reached more than 1000 km from their source. Our land-sea correlation also allow to provide an independant temporal constraint to the regional d18O records

Marine tephra offshore Ecuador and Southern Colombia: first trench-to-arc correlations and implication for the magnitude of major eruptions

International audienceMajor eruptions in the Andes are mainly characterized by the emission of large volumes of gas and volcanic ash. The plume may reach the stratosphere and be transported by winds. In Ecuador, the prevailing winds are westward, and the volcanic ash, also called tephra, is transported towards the Pacific Ocean. Vallejo (2011) studied tephra layers present in marine terraces and proposed a first draft of the identification of their source in the Cordillera. However tephras deposited onshore may have been remobilized, eroded or covered by younger deposits. There are therefore several interests in studying tephras recorded in marine sediments : it allows to (1) know the age and source of major eruptions whose products reached the coast, (2) know the distribution of fallout from each major eruption, (3) estimate the volume of largest events, (4) participate to better assess the current volcanic hazard, and (5) provide temporal constraints on continental or marine sediments that cannot be dated by radiocarbon. To study the tephra layers recorded in marine sediments I have described the glass morphology and the mineralogy of tephra beds. To determine the source of the eruptions, I have used data published onshore (e.g., Hidalgo et al., 2008; Hall et Mothes, 2008; Robin et al., 2010). As each volcano has its own geochemical signature when we combine major, trace and isotope data, I compared them with geochemical analyses performed on distal tephra recorded in marine sediments. To determine the age of distal tephra beds, we have performed 14C ages on foraminifera present above and below the bed for tephra emitted during the past 50 ka, and d18O and biostratigraphy for the older deposits. In this presentation, I first presented our results obtained on cores collected during Amadeus (2005) and Atacames (2012) oceanic campaigns along the Ecuadorian margin, and recently published (Bablon et al., 2022). We have sampled 28 tephra layers, from coring sites that cover 5 degrees of latitude, from the southern half of Ecuador to southern Colombia. We observed four main lithofacies: isolated lenses that typical of bioturbation, layers with sharp and sometimes diffuse contacts in the upper part that correspond to primary deposits of tephra fallout, and successions of thin laminated layers that correspond to tephra layers reworked by turbidity currents, and that have not been sampled. Volcanic glass shards have various morphologies depending on the density of vesicles and their deformation, such as block-shaped glass without bubbles, pumice-shaped glass, or glass with completely elongated bubbles. The glass morphology of each tephra allows us to propose a first correlation of layers between each marine core. Concerning the geochemistry, glasses are mostly rhyolitic and belong to the low potassic series typical of the volcanic front, and to high potassic series typical of the eastern cordillera. This distinction between the eastern and western cordillera is also found in their trace element signature. To identify the source volcano, we used Sr and Pb isotopes. On The compositional fields of the volcanoes products overlap little and thus allows us to refine the correlations. We show that distal marine tephra come from the Cerro Machin in Colombia, and from Pichincha, Atacazo, and Cotopaxi volcanoes in Ecuador. Together with the determination of the sources, the radiocarbon dating of sediments allowed us to show that the oldest tephras belonged to the about 8 ka eruption of Cotopaxi, and the youngest correspond to the 10th century eruption of Pichincha. Using the spatial distribution of tephra, we made isopach maps of the fourth major eruptions of Pichincha, Atacazo and Cotopaxi, and we estimated their volumes. They vary between 1.3 and 6 km3, which corresponds to volcanic explosivity indexes of 5, thus eruptions which would be particularly destructive today. A perspective for our work is to study of turbidite beds present in the Holocene cores along the coast. As such deposits are emplaced during major earthquakes, and we can therefore use their correlation to identify past seiscally active areas.Unfortunately, some major Holocene eruptions described in the Cordillera and constitute stratigraphic markers have not been recorded in marine sediments. Tephra layers may have been destructed during drilling such as the very young 700 BP eruption of Quilotoa, they may have been dispersed by ocean currents, or tephra were not present in the cores du to a restricted distribution of deposits, for example for the 3000 BP eruption of Cuicocha (Vallejo, 2011).In the second part of my presentation, I focused on another case study, performed at ODP site 1239, above the Carnegie Ridge. This core is much deeper as it reaches 500 m, and sediments deposited about 10 Myr ago. It contains 24 tephra layers, and we focused on the thickest, 18 cm-thick at 7 m deep (Schipboard Scientific Party, 2003; Bablon et al., 2020). The main volcanic structure that could be the source of such a thick deposit is the Chalupas caldera, located in the Eastern Cordillera, near Cotopaxi volcano. About 50 km southwest of the caldera, we sampled the ignimbrite and dated the glass shards at 216 +/- 5 ka using the K-Ar dating method applied on glass shards. In order to verify if the ignimbrite and marine tephra of ODP Site 1239 belong to the same eruption, we have compared their geochemistry, and we have shown that their major and trace element contents are very close. To check the reliability of this land-sea correlation, we have also compared their ages. Variations of d18O are related to climate changes linked to the Earth's orbital forcing. We then used d18O data available to know the age of sediments as a function of depth. The stratigraphic position of the tephra layer corresponds to the 7d isotopic stage that occured at 220 ka, in agreement with our K-Ar age obtained onland. We then have shown that the 216 +/- 5 ka eruption of Chalupas is the largest of the Quaternary in northern Andes, with products that reached more than 1000 km from their source. Our land-sea correlation also allow to provide an independant temporal constraint to the regional d18O records