A5079783310- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- Treatment of Major Depression
- Enzyme Structure and Function
- Statistical Methods in Clinical Trials
- Medical Imaging Techniques and Applications
- Sleep and Wakefulness Research
- Sleep and related disorders
- X-ray Diffraction in Crystallography
- Neuropeptides and Animal Physiology
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Photochromic and Fluorescence Chemistry
- Statistical Methods and Bayesian Inference
- Mental Health Research Topics
- Monoclonal and Polyclonal Antibodies Research
- Circadian rhythm and melatonin
- T-cell and B-cell Immunology
- Genetic Neurodegenerative Diseases
- Advanced MRI Techniques and Applications
- Proteins in Food Systems
- Neuroscience and Neuropharmacology Research
- Health Systems, Economic Evaluations, Quality of Life
- Immune Cell Function and Interaction
École Polytechnique Fédérale de Lausanne
2018-2023
Age UK
2018-2021
Institut de Physique
2020
Scuola Internazionale Superiore di Studi Avanzati
2016-2019
GlaxoSmithKline (United Kingdom)
2011-2018
Istituto Nazionale di Fisica Nucleare, Galileo Galilei Institute for Theoretical Physics
2018
University of Padua
2013-2015
University of Pavia
2015
GlaxoSmithKline (India)
2014
GlaxoSmithKline (Italy)
2002-2013
ParABS systems facilitate chromosome segregation and plasmid partitioning in bacteria archaea. ParB protein binds centromeric parS DNA sequences spreads to flanking DNA. We show that is an enzyme hydrolyzes cytidine triphosphate (CTP) diphosphate (CDP). stimulates cooperative CTP binding by hydrolysis. A nucleotide cocrystal structure elucidates the catalytic center of dimerization-dependent CTPase. Single-molecule imaging biochemical assays recapitulate features spreading from presence but...
We rationalize the behaviour of protonated merocyanines in water through cross-validation <sup>1</sup>H NMR, UV-Vis and pH measurements, show their capability to act as reversible photoacids along light/dark cycles can be described by a four-state model.
Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which involved sphingolipid biosynthesis, are associated with intellectual disability, but pathogenic mechanism remains obscure. Here, we characterize 31 individuals de novo missense variants CERT1. Several fall into a previously uncharacterized dimeric helical domain that enables...
To assess the acute effects of SB-649868 in male subjects with Primary Insomnia regard to (1) objective and subjective sleep parameters, (2) safety tolerability, (3) next-day residual effects.
Three-component ParABS systems are widely distributed factors for plasmid partitioning and chromosome segregation in bacteria. ParB acts as adaptor protein between the 16–base pair centromeric parS DNA sequences proteins ParA Smc (structural maintenance of chromosomes). Upon cytidine triphosphate (CTP) binding, dimers form clamps that spread onto -flanking by sliding, thus assembling so-called partition complex. We show here CTP hydrolysis is essential efficient but largely dispensable...
Abstract ATP-Binding Cassette (ABC) transporters are a broad family of biological machines, found in most prokaryotic and eukaryotic cells, performing the crucial import or export substrates through both plasma organellar membranes, maintaining steady concentration gradient driven by ATP hydrolysis. Building upon present biophysical biochemical characterization ABC transporters, we propose here model whose solution reveals that these machines an exact molecular realization autonomous Maxwell...
Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies patients with major depressive disorder (MDD). Displacement [ 11 C]GR205171 binding indicated that oral doses 30–60 mg/day provided >99% receptor occupancy ≥24 h....
Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill early promise demonstrated II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete occupancy was studied 2 randomized, placebo-controlled, double-blind, trials depressed outpatients test hypothesis is required achieve antidepressant efficacy. Study 092 used an interactive voice response system recruit patients...
We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes Safety Estrogen Lupus National Assessment-SLE Disease Activity Index score, number/severity adverse...
A visible light-switchable buffer system based on a merocyanine photoacid is presented. Para-substitution of the indolium side with methoxy group affords compound suitable for making hydrolytically stable aqueous buffers whose pH can be tuned between 7 and 4 using 500 nm light.
The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials novel dual receptor antagonist SB-649868 has demonstrated preclinical potential for treatment sleep disorders. trial designs included single ascending dose escalation study (dose range: 10–80 mg fed fasted states) multiple repeat 5–30 state) enrolling total 103 male volunteer subjects. was well tolerated at all doses this...
Positron emission tomography (PET) is used in drug development to assist dose selection and establish the relationship between blood tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using data obtained after administration single (SD). A PET study incorporating sequential adaptive design was conducted 10 healthy male adults who underwent 4 scans with [(11)C]DASB...
Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines safety, tolerability efficacy patients with active RA.This was (Parts A, B C), multicenter study. Part A were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate tolerability, efficacy,...
The devising of efficient concerted rotation moves that modify only selected local portions chain molecules is a long studied problem. Possible applications range from speeding the uncorrelated sampling polymeric dense systems to loop reconstruction and structure refinement in protein modeling. Here, we propose validate, on few pedagogical examples, novel numerical strategy generalizes notion rotation. usage Denavit-Hartenberg parameters for description allows all possible choices subset...
GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in first-in-human study evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model employed assess target engagement the ability of compound inhibit recruitment inflammatory CCR6 expressing cells.This randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial 48 healthy male...
The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, is a potential therapeutic target for inflammatory fibrotic diseases. aim of this first-time-in-human experimental medicine study was to assess the safety, tolerability, pharmacokinetics engagement single subcutaneous doses GSK2330811, an anti-OSM monoclonal antibody, in healthy subjects.This phase I, randomized, double-blind, placebo-controlled, single-dose escalation, subcutaneously administered GSK2330811...
The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand a GlyT-1 PET molecular imaging tool aid drug development and dose selection. We report on [(11) C]GSK931145 novel probe primate man. Primate studies were performed determine level of specific binding following homologous competition with GSK931145 plasma-occupancy relationship inhibitor GSK1018921. Human test-retest reproducibility entered human brain...
Investigate the hypnotic effects of repeated doses neurokinin-1 receptor antagonist, vestipitant, in primary insomnia.
Pro-inflammatory cytokines (PICs) may play important pathophysiological roles in some forms of Major Depressive Disorder (MDD). The p38 MAPK inhibitor losmapimod (GW856553) attenuates the pro-inflammatory response humans by reducing PIC production. Losmapimod (7.5 mg BD) was administered for 6 weeks two randomised, placebo-controlled trials subjects with MDD enriched symptoms loss energy/interest and psychomotor retardation (Studies 574 009). Primary efficacy endpoints were Bech 6-item...
<i>N</i>-[[(2<i>S</i>)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [<sup>14</sup>C]SB-649868 was determined in eight healthy male subjects using an open-label study design after single oral dose 30 mg. Blood, urine, feces were collected at frequent intervals dosing, samples analyzed by high-performance liquid...
Positron emission tomography (PET) is an imaging technique that used to investigate ligand–receptor binding in the living brain and determine time course of plasma concentration/receptor occupancy (RO). The purpose this work was demonstrate added value adaptive-optimal design for PET scan timings dose selection over traditional study designs involving fixed or educated selections doses. A kon–koff model relating concentration data applied generate simulated data. Optimization performed on...
GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- active-controlled, double-blind studies examined the efficacy safety in outpatients (aged 18–64 years) diagnosis major depressive episode associated disorder (MDD). Patients were randomized 1:1:1 to placebo, (1–2 mg/d), or active control (Study 1: venlafaxine XR 150–225 mg/d; Study 2: paroxetine 20–30 mg/d). did not significantly...