Martinez N

References (9)

Title : From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects - Pont_2021_Eur.J.Med.Chem_225_113779
Author(s) : Pont C , Ginex T , Grinan-Ferre C , Scheiner M , Mattellone A , Martinez N , Arce EM , Soriano-Fernandez Y , Naldi M , De Simone A , Barenys M , Gomez-Catalan J , Perez B , Sabate R , Andrisano V , Loza MI , Brea J , Bartolini M , Bolognesi ML , Decker M , Pallas M , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 225 :113779 , 2021
Abstract : Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Abeta42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
ESTHER : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedSearch : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedID: 34418785

Title : Impact of Sucrose as Osmolyte on Molecular Dynamics of Mouse Acetylcholinesterase - Lushchekina_2020_Biomolecules_10_
Author(s) : Lushchekina SV , Inidjel G , Martinez N , Masson P , Trovaslet-Leroy M , Nachon F , Koza MM , Seydel T , Peters J
Ref : Biomolecules , 10 : , 2020
Abstract : The enzyme model, mouse acetylcholinesterase, which exhibits its active site at the bottom of a narrow gorge, was investigated in the presence of different concentrations of sucrose to shed light on the protein and water dynamics in cholinesterases. The study was conducted by incoherent neutron scattering, giving access to molecular dynamics within the time scale of sub-nano to nanoseconds, in comparison with molecular dynamics simulations. With increasing sucrose concentration, we found non-linear effects, e.g., first a decrease in the dynamics at 5 wt% followed by a gain at 10 wt% sucrose. Direct comparisons with simulations permitted us to understand the following findings: at 5 wt%, sugar molecules interact with the protein surface through water molecules and damp the motions to reduce the overall protein mobility, although the motions inside the gorge are enhanced due to water depletion. When going to 10 wt% of sucrose, some water molecules at the protein surface are replaced by sugar molecules. By penetrating the protein surface, they disrupt some of the intra-protein contacts, and induce new ones, creating new pathways for correlated motions, and therefore, increasing the dynamics. This exhaustive study allowed for an explanation of the detail interactions leading to the observed non-linear behavior.
ESTHER : Lushchekina_2020_Biomolecules_10_
PubMedSearch : Lushchekina_2020_Biomolecules_10_
PubMedID: 33322722

Title : Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering - Andersson_2018_J.Phys.Chem.B_122_8516
Author(s) : Andersson CD , Martinez N , Zeller D , Allgardsson A , Koza MM , Frick B , Ekstrom F , Peters J , Linusson A
Ref : J Phys Chem B , 122 :8516 , 2018
Abstract : The enzyme acetylcholinesterase (AChE) is essential in humans and animals because it catalyzes the breakdown of the nerve-signaling substance acetylcholine. Small molecules that inhibit the function of AChE are important for their use as drugs in the, for example, symptomatic treatment of Alzheimer's disease. New and improved inhibitors are warranted, mainly because of severe side effects of current drugs. In the present study, we have investigated if and how two enantiomeric inhibitors of AChE influence the overall dynamics of noncovalent complexes, using elastic incoherent neutron scattering. A fruitful combination of univariate models, including a newly developed non-Gaussian model for atomic fluctuations, and multivariate methods (principal component analysis and discriminant analysis) was crucial to analyze the fine details of the data. The study revealed a small but clear increase in the dynamics of the inhibited enzyme compared to that of the noninhibited enzyme and contributed to the fundamental knowledge of the mechanisms of AChE-inhibitor binding valuable for the future development of inhibitors.
ESTHER : Andersson_2018_J.Phys.Chem.B_122_8516
PubMedSearch : Andersson_2018_J.Phys.Chem.B_122_8516
PubMedID: 30110543

Title : Dynamics of human acetylcholinesterase bound to non-covalent and covalent inhibitors shedding light on changes to the water network structure - Peters_2016_Phys.Chem.Chem.Phys_18_12992
Author(s) : Peters J , Martinez N , Trovaslet M , Scannapieco K , Koza MM , Masson P , Nachon F
Ref : Phys Chem Chem Phys , 18 :12992 , 2016
Abstract : We investigated the effects of non-covalent reversible and covalent irreversible inhibitors on human acetylcholinesterase and human butyrylcholinesterase. Remarkably a non-covalent inhibitor, Huperzine A, has almost no effect on the molecular dynamics of the protein, whereas the covalently binding nerve agent soman renders the molecular structure stiffer in its aged form. The modified movements were studied by incoherent neutron scattering on different time scales and they indicate a stabilization and stiffening of aged human acetylcholinesterase. It is not straightforward to understand the forces leading to this strong effect. In addition to the specific interactions of the adduct within the protein, some indications point towards an extensive water structure change for the aged conjugate as water Bragg peaks appeared at cryogenic temperature despite an identical initial hydration state for all samples. Such a change associated to an apparent increase in free water volume upon aging suggests higher ordering of the hydration shell that leads to the stiffening of protein. Thus, several additive contributions seem responsible for the improved flexibility or stiffening effect of the inhibitors rather than a single interaction.
ESTHER : Peters_2016_Phys.Chem.Chem.Phys_18_12992
PubMedSearch : Peters_2016_Phys.Chem.Chem.Phys_18_12992
PubMedID: 27109895

Title : Standard versus continuous administration of capecitabine in metastatic breast cancer (GEICAM\/2009-05): a randomized, noninferiority phase II trial with a pharmacogenetic analysis - Martin_2015_Oncologist_20_111
Author(s) : Martin M , Martinez N , Ramos M , Calvo L , Lluch A , Zamora P , Munoz M , Carrasco E , Caballero R , Garcia-Saenz JA , Guerra E , Caronia D , Casado A , Ruiz-Borrego M , Hernando B , Chacon JI , De la Torre-Montero JC , Jimeno MA , Heras L , Alonso R , De la Haba J , Pita G , Constenla M , Gonzalez-Neira A
Ref : Oncologist , 20 :111 , 2015
Abstract : BACKGROUND: The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy.
METHODS: We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed.
RESULTS: The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3-4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3-4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5' untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. CONCLUSION: Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.
ESTHER : Martin_2015_Oncologist_20_111
PubMedSearch : Martin_2015_Oncologist_20_111
PubMedID: 25601966

Title : Pressure-induced molten globule state of human acetylcholinesterase: structural and dynamical changes monitored by neutron scattering - Marion_2015_Phys.Chem.Chem.Phys_17_3157
Author(s) : Marion J , Trovaslet M , Martinez N , Masson P , Schweins R , Nachon F , Trapp M , Peters J
Ref : Phys Chem Chem Phys , 17 :3157 , 2015
Abstract : We used small-angle neutron scattering (SANS) to study the effects of high hydrostatic pressure on the structure of human acetylcholinesterase (hAChE). At atmospheric pressure, our SANS results obtained on D11 at ILL (Grenoble, France) give a radius of gyration close to that calculated for a mixture of monomers, dimers and tetramers of the enzyme, suggesting a good agreement between hAChE crystal structure and its conformation in solution. Applying high pressure to the sample we found a global compression of about 11% of the enzyme up to a pressure of 900 bar and then again an extension up to 2.1 kbar indicating unfolding of the tertiary structure due to a molten globule (MG) state. On the other hand, we studied the influence of pressure up to 6 kbar on the dynamics of this enzyme, on the backscattering spectrometer IN13 at ILL. For the first time, we used elastic incoherent neutron scattering (EINS) to probe the differences between hAChE in its folded state (N), its high-pressure induced MG state and its unfolded state (U). Especially around the MG state at 1750 bar we found a significant increase in the dynamics, indicating a partial unfolding. A four-step-model is suggested to describe the changes in the protein.
ESTHER : Marion_2015_Phys.Chem.Chem.Phys_17_3157
PubMedSearch : Marion_2015_Phys.Chem.Chem.Phys_17_3157
PubMedID: 25515378

Title : Genome Sequence Analysis of the Biogenic Amine-Degrading Strain Lactobacillus casei 5b - Ladero_2014_Genome.Announc_2_e01199
Author(s) : Ladero V , Herrero-Fresno A , Martinez N , Del Rio B , Linares DM , Fernandez M , Martin MC , Alvarez MA
Ref : Genome Announc , 2 : , 2014
Abstract : We here report a 3.02-Mbp annotated draft assembly of the Lactobacillus casei 5b genome. The sequence of this biogenic amine-degrading dairy isolate may help identify the mechanisms involved in the catabolism of biogenic amines and perhaps shed light on ways to reduce the presence of these toxic compounds in food.
ESTHER : Ladero_2014_Genome.Announc_2_e01199
PubMedSearch : Ladero_2014_Genome.Announc_2_e01199
PubMedID: 24435875
Gene_locus related to this paper: lacc3-q03b36 , laccb-b3wcx2 , lacrh-pepr , lacca-b5qt93 , lacca-k0n1x0 , lacpa-s2ter8 , lacpa-s2rz88

Title : Correlation of the dynamics of native human acetylcholinesterase and its inhibited huperzine A counterpart from sub-picoseconds to nanoseconds - Trapp_2014_J.R.Soc.Interface_11_
Author(s) : Trapp M , Tehei M , Trovaslet M , Nachon F , Martinez N , Koza MM , Weik M , Masson P , Peters J
Ref : J R Soc Interface , 11 : , 2014
Abstract : It is a long debated question whether catalytic activities of enzymes, which lie on the millisecond timescale, are possibly already reflected in variations in atomic thermal fluctuations on the pico- to nanosecond timescale. To shed light on this puzzle, the enzyme human acetylcholinesterase in its wild-type form and complexed with the inhibitor huperzine A were investigated by various neutron scattering techniques and molecular dynamics simulations. Previous results on elastic neutron scattering at various timescales and simulations suggest that dynamical processes are not affected on average by the presence of the ligand within the considered time ranges between 10 ps and 1 ns. In the work presented here, the focus was laid on quasi-elastic (QENS) and inelastic neutron scattering (INS). These techniques give access to different kinds of individual diffusive motions and to the density of states of collective motions at the sub-picoseconds timescale. Hence, they permit going beyond the first approach of looking at mean square displacements. For both samples, the autocorrelation function was well described by a stretched-exponential function indicating a linkage between the timescales of fast and slow functional relaxation dynamics. The findings of the QENS and INS investigation are discussed in relation to the results of our earlier elastic incoherent neutron scattering and molecular dynamics simulations.
ESTHER : Trapp_2014_J.R.Soc.Interface_11_
PubMedSearch : Trapp_2014_J.R.Soc.Interface_11_
PubMedID: 24872501

Title : Randomized, phase II trial comparing continuous versus intermittent capecitabine (X) monotherapy for metastatic breast cancer (MBC): Results from the GEICAM 2009-05 study - Martin_2011_J.Clin.Oncol_29_1008
Author(s) : Martin M , Martinez N , Ramos M , Calvo L , Lluch A , Zamora P , Munoz-Mateu M , Caronia D , Carrasco EM , Garcia Saenz JA , Casado A , Chacon I , Hernando B , Ruiz-Borrego M , Gonzalez-Neira A
Ref : J Clin Oncol , 29 :1008 , 2011
Abstract : 1008 Background: X, 1,250 mg/m2 bid, d1-14 q21d (Xint) is an approved regimen in MBC, but is associated with dose-limiting toxicities. Thus, we designed this randomized phase II study to investigate whether continuous dosing of X (Xcont) could reduce the severity of side effects while maintaining the total cumulative dose and efficacy.
METHODS: Pts with evaluable MBC, normal organ function, ECOG PS <=2 and <=2 prior regimens in the metastatic setting were eligible and randomized to X 800 mg/m2 bid, d1-21 q21d Xcont or Xint q3w. Study endpoints: safety (CTCAE v2.0), TTP, ORR, PFS, DOR, OS.
RESULTS: 196 pts were randomized to Xcont (n=99) or Xint (n=97) until progression or unacceptable toxicity. Baseline characteristics were balanced between Xcont and Xint with a median age of 60 yrs (29-88); 21% and 22% were hormone receptor negative; 20% and 16% had prior neoadjuvant chemo; adjuvant therapy had been administered in 76% and 77%, respectively; 56% had visceral involvement in each arm. X was administered as first-line in 45% and 36% of pts, respectively. Prior anthracyclines plus taxanes had been administered to 80% and 89%, in Xcont and Xint, respectively. This preliminary analysis is based on the ITT population: Best RECIST ORR was 29% and 25%, with Xint and Xcont, respectively. Median PFS: 244 vs 187 days (HR 0.69, 95% CI 0.46-1.05), respectively. The relationship between X-induced HFS and 13 polymorphisms in the genes involved in the drug metabolism and target gene (the carboxylesterase 2, cytidine deaminase, thymidine phosphorylase, dihydropyrimidine dehydrogenase gene and thymidylate synthase) will be reported. Grade 3/4 toxicities that differ between groups are reported in the table.
CONCLUSIONS: The ongoing evaluation suggests that Xcont has a lower incidence of related AEs. It is too early to draw any conclusion about efficacy, mature data will be presented at the meeting. [Table: see text].
ESTHER : Martin_2011_J.Clin.Oncol_29_1008
PubMedSearch : Martin_2011_J.Clin.Oncol_29_1008
PubMedID: 28020778