Publications by authors named "Gonzalo Colmenarejo"

38 Publications

Metabolic Health Together with a Lipid Genetic Risk Score Predicts Survival of Small Cell Lung Cancer Patients.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, E-28049 Madrid, Spain.

Small cell lung cancer (SCLC) prognosis is the poorest of all types of lung cancer. Its clinical management remains heterogeneous and therefore, the capability to predict survival would be of great clinical value. Metabolic health (MH) status and lipid metabolism are two relevant factors in cancer prevention and prognosis. Nevertheless, their contributions in SCLC outcome have not yet been analyzed. We analyzed MH status and a transcriptomic panel of lipid metabolism genes in SCLC patients, and we developed a predictive genetic risk score (GRS). MH and two lipid metabolism genes, racemase and perilipin 1, are biomarkers of SCLC survival (HR = 1.99 (CI95%: 1.11-3.61) = 0.02, HR = 0.36 (CI95%: 0.19-0.67), = 0.03 and HR = 0.21 (CI95%: 0.09-0.47), respectively). Importantly, a lipid GRS of these genes predict better survival (c-index = 0.691). Finally, in a Cox multivariate regression model, MH, lipid GRS and smoking history are the main predictors of SCLC survival (c-index = 0.702). Our results indicate that the control of MH, lipid gene expression and environmental factors associated with lifestyle is crucial for increased SCLC survival. Here, we propose for the first time, a metabolic precision approach for SCLC patients.
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http://dx.doi.org/10.3390/cancers13051112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961979PMC
March 2021

Ranking of a wide multidomain set of predictor variables of children obesity by machine learning variable importance techniques.

Sci Rep 2021 Jan 21;11(1):1910. Epub 2021 Jan 21.

Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, CEI UAM+CSIC, 28049, Madrid, Spain.

The increased prevalence of childhood obesity is expected to translate in the near future into a concomitant soaring of multiple cardio-metabolic diseases. Obesity has a complex, multifactorial etiology, that includes multiple and multidomain potential risk factors: genetics, dietary and physical activity habits, socio-economic environment, lifestyle, etc. In addition, all these factors are expected to exert their influence through a specific and especially convoluted way during childhood, given the fast growth along this period. Machine Learning methods are the appropriate tools to model this complexity, given their ability to cope with high-dimensional, non-linear data. Here, we have analyzed by Machine Learning a sample of 221 children (6-9 years) from Madrid, Spain. Both Random Forest and Gradient Boosting Machine models have been derived to predict the body mass index from a wide set of 190 multidomain variables (including age, sex, genetic polymorphisms, lifestyle, socio-economic, diet, exercise, and gestation ones). A consensus relative importance of the predictors has been estimated through variable importance measures, implemented robustly through an iterative process that included permutation and multiple imputation. We expect this analysis will help to shed light on the most important variables associated to childhood obesity, in order to choose better treatments for its prevention.
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http://dx.doi.org/10.1038/s41598-021-81205-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820584PMC
January 2021

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non-small cell lung cancer.

Mol Oncol 2020 12 30;14(12):3135-3152. Epub 2020 Oct 30.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid-lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remains unclear. Here, we found that simvastatin treatment effectively promoted antiproliferative effects and modulated lipid metabolism-related pathways in non-small cell lung cancer (NSCLC) cells and that the antiproliferative effects of statins were potentiated by overexpression of acyl-CoA synthetase long-chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high-grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.
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http://dx.doi.org/10.1002/1878-0261.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718959PMC
December 2020

A Potential Endurance Algorithm Prediction in the Field of Sports Performance.

Front Genet 2020 11;11:711. Epub 2020 Aug 11.

Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, CEI UAM + CSIC, Madrid, Spain.

Sport performance is influenced by several factors, including genetic susceptibility. In the past years, specific single nucleotide polymorphisms have been associated to sport performance; however, these effects should be considered in multivariable prediction systems since they are related to a polygenic inheritance. The aim of this study was to design a genetic endurance prediction score (GES) of endurance performance and analyze its association with anthropometric, nutritional and sport efficiency variables in a cross-sectional study within fifteen male cyclists. A statistically significant positive relationship between GES and the VO maximum ( = 0.033), VO VT1 ( = 0.049) and VO VT2 ( < 0.001) was observed. Moreover, additional remarkable associations between genotype and the anthropometric, nutritional and sport performance variables, were achieved. In addition, an interesting link between the habit of consuming caffeinated beverages and the GES was observed. The outcomes of the present study indicate a potential use of this genetic prediction algorithm in the sports' field, which may facilitate the finding of genetically talented athletes, improve their training and food habits, as well as help in the improvement of physical conditions of amateurs.
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http://dx.doi.org/10.3389/fgene.2020.00711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431952PMC
August 2020

Machine Learning Models to Predict Childhood and Adolescent Obesity: A Review.

Nutrients 2020 Aug 16;12(8). Epub 2020 Aug 16.

Biostatistics and Bioinformatics Unit, IMDEA Food, CEI UAM+CSIC, E28049 Madrid, Spain.

The prevalence of childhood and adolescence overweight an obesity is raising at an alarming rate in many countries. This poses a serious threat to the current and near-future health systems, given the association of these conditions with different comorbidities (cardiovascular diseases, type II diabetes, and metabolic syndrome) and even death. In order to design appropriate strategies for its prevention, as well as understand its origins, the development of predictive models for childhood/adolescent overweight/obesity and related outcomes is of extreme value. Obesity has a complex etiology, and in the case of childhood and adolescence obesity, this etiology includes also specific factors like (pre)-gestational ones; weaning; and the huge anthropometric, metabolic, and hormonal changes that during this period the body suffers. In this way, Machine Learning models are becoming extremely useful tools in this area, given their excellent predictive power; ability to model complex, nonlinear relationships between variables; and capacity to deal with high-dimensional data typical in this area. This is especially important given the recent appearance of large repositories of Electronic Health Records (EHR) that allow the development of models using datasets with many instances and predictor variables, from which Deep Learning variants can generate extremely accurate predictions. In the current work, the area of Machine Learning models to predict childhood and adolescent obesity and related outcomes is comprehensively and critically reviewed, including the latest ones using Deep Learning with EHR. These models are compared with the traditional statistical ones that used mainly logistic regression. The main features and applications appearing from these models are described, and the future opportunities are discussed.
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http://dx.doi.org/10.3390/nu12082466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469049PMC
August 2020

Analysis of Nuisance Substructures and Aggregators in a Comprehensive Database of Food Chemical Compounds.

J Agric Food Chem 2020 Aug 5;68(33):8812-8824. Epub 2020 Aug 5.

Biostatistics and Bioinformatics Unit, IMDEA Food CEI UAM+CSIC, E28049 Madrid, Spain.

The mechanistic understanding of the biological effects of foods involves the testing of food compounds in biochemical and biological assays. Positive results in these assays can be artifactual due to some properties of the compound: namely chemical reactivity, membrane disruption, redox cycling, etc., or through the formation of colloidal aggregates. Within the drug discovery field, a wide set of so-called "nuisance" filters have been developed to identify substructures prone to assay artifacts and/or promiscuity, e.g., the pan-assay interference compounds (PAINS) and others. In the subarea of natural products, a similar concept is the so-called invalid metabolic panaceas (IMPs). Finally, tools to identify putative aggregators have also been developed. Here, we analyzed the presence of nuisance substructures, IMPs, and aggregators in a large database of food compounds (the FooDB), which should be useful to the researchers working in the field, in order to be aware of possible artifact/promiscuity issues in their assays.
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http://dx.doi.org/10.1021/acs.jafc.0c02521DOI Listing
August 2020

Clinical-pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer.

Cancer Biol Med 2020 05;17(2):444-457

Infanta Sofía University Hospital, San Sebastián De Los Reyes, Madrid 28702, Spain.

Long-term survivors (LS) of non-small cell lung cancer (NSCLC) without driver alterations, displaying an overall survival (OS) of more than 3 years, comprise around 10% of cases in several series treated with chemotherapy. There are classical prognosis factors for these cases [stage, Eastern Cooperative Oncology Group (ECOG), etc.], but more data are required in the literature. In this multi-center study, we focused on LS of advanced NSCLC with OS above 36 months to perform a clinical-pathological and molecular characterization. In the first step, we conducted a clinical-pathological characterization of the patients. Afterwards, we carried out a genetic analysis by comparing LS to a sample of short-term survivors (SS) (with an OS less than 9 months). We initially used whole-genome RNA-seq to identify differentiating profiles of LS and SS, and later confirmed these with reverse transcription-polymerase chain reaction (RT-PCR) for the rest of the samples. A total of 94 patients were included, who were mainly men, former smokers, having adenocarcinoma (AC)-type NSCLC with an ECOG of 0-1. We obtained an initial differential transcriptome expression, displaying 5 over- and 33 under-expressed genes involved in different pathways: namely, the secretin receptor, surfactant protein, trefoil factor 1 (TFF1), serpin, Ca-channels, and Toll-like receptor (TLRs) families. Finally, RT-PCR analysis of 40 (20 LS/20 SS) samples confirmed that four genes (surfactant proteins and SFTP) were significantly down-regulated in SS compared to LS by using an analysis of covariance (ANCOVA) model: ( = 0.023), ( = 0.027), ( = 0.02), and ( = 0.047). We present a sequential genetic analysis of a sample of NSCLC LS with no driver alterations, obtaining a differential RNA-seq/RT-PCR profile showing an abnormal expression of SF genes.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2019.0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309469PMC
May 2020

Polymorphic Appetite Effects on Waist Circumference Depend on rs3749474 CLOCK Gene Variant.

Nutrients 2020 Jun 21;12(6). Epub 2020 Jun 21.

IMDEA-Food Institute, CEI UAM+CSIC, 28049 Madrid, Spain.

Chronobiological aspects controlled by genes may influence obesity incidence. Although there are studies that show an association between the expression of these genes and energy intake, waist circumference or abdominal obesity phenotypes, interactions with appetite have been insufficiently investigated in relation to chrononutrition. The objective was to identify interactions between genetic variants involved in appetite status. A total of 442 subjects (329 women, 113 men; aged 18 to 65 years) were recruited. Anthropometric, dietary and lifestyle data were collected by trained nutritionists. Participants were classified according to their appetite feelings with a Likert scale. Multiple linear regression models were used to examine associations of the type genotype x appetite status on adiposity-related variables. values were corrected by the Bonferroni method. A significant influence was found concerning the effects of appetite on waist circumference with respect to rs3749474 polymorphism ( < 0.001). An additive model analysis (adjusted by age, gender, exercise and energy intake) showed that risk allele carriers, increased the waist circumference around 14 cm ( = 14.1, CI = 6.3-22.0) by each increment in the level of appetite. The effects of appetite on waist circumference may be partly modulated by the rs3749474 polymorphism.
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http://dx.doi.org/10.3390/nu12061846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353411PMC
June 2020

The Q223R Polymorphism of the Leptin Receptor Gene as a Predictor of Weight Gain in Childhood Obesity and the Identification of Possible Factors Involved.

Genes (Basel) 2020 05 17;11(5). Epub 2020 May 17.

Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain.

(1) Background: Childhood rapid weight gain during development has been postulated as a predictor of obesity. The objective of this study was to investigate the effect of single nucleotide polymorphisms (SNPs) on the annual weight gain and height growth, as well as identifying possible lifestyle factors involved. (2) Methods: As part of the GENYAL study, 221 children (6-8 years old) of Madrid (Spain) were enrolled. A total of 11 SNPs associated with high childhood body mass indexes (BMIs) were assessed. Anthropometric measurements, dietary and physical activity data, were collected in 2017 and 2018. Bonferroni-corrected linear models were used to fit the data. (3) Results: A significant association between the Q223R and the weight growth was found, showing a different behavior between GA and GG genotypes ( = 0.001). Regarding lifestyle factors, an interaction between Q223R genotypes and total active weekly hours/week to predict the weight growth (kg/year) was observed ( = 0.023). In all the genotypes, a beneficial effect against rapid weight growth was observed, but the effect size of the interaction was much more significant in homozygous (GG) minor homozygous (β = -0.61 (-0.95, -0.26) versus heterozygous (AG) and wild-type homozygous (AA) genotypes (β = -0.07 (-0.24, 0.09) and β = -0.12 (-0.32, 0.08), respectively). (4) Conclusions: These results may contribute to more personalized recommendations to prevent childhood obesity.
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http://dx.doi.org/10.3390/genes11050560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288327PMC
May 2020

Genetic Polymorphisms, Mediterranean Diet and Microbiota-Associated Urolithin Metabotypes can Predict Obesity in Childhood-Adolescence.

Sci Rep 2020 05 12;10(1):7850. Epub 2020 May 12.

Laboratory of Food & Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, 30100, Campus de Espinardo, Murcia, Spain.

Environmental and genetic factors are associated with pandemic obesity since childhood. However, the association of overweight-obesity with these factors, acting as a consortium, has been scarcely studied in children. We aimed here to assess the probabilities of being overweighed-obese in a randomly recruited cohort of Spanish children and adolescents (n = 415, 5-17 years-old) by estimating the odds ratios for different predictor variables, and their relative importance in the prediction. The predictor variables were ethnicity, age, sex, adherence to the Mediterranean diet (KIDMED), physical activity, urolithin metabotypes (UM-A, UM-B and UM-0) as biomarkers of the gut microbiota, and 53 single-nucleotide polymorphisms (SNPs) from 43 genes mainly related to obesity and cardiometabolic diseases. A proportional-odds logistic ordinal regression, validated through bootstrap, was used to model the data. While every variable was not independently associated with overweight-obesity, however, the ordinal logistic model revealed that overweight-obesity prevalence was related to being a young boy with either UM-B or UM-0, low KIDMED score and high contribution of a consortium of 24 SNPs, being rs1801253-ADRB1, rs4343-ACE, rs8061518-FTO, rs1130864-CRP, rs659366-UCP2, rs6131-SELP, rs12535708-LEP, rs1501299-ADIPOQ, rs708272-CETP and rs2241766-ADIPOQ the top-ten contributing SNPs. Additional research should confirm and complete this model by including dietary interventions and the individuals' gut microbiota composition.
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http://dx.doi.org/10.1038/s41598-020-64833-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217888PMC
May 2020

Polymorphism of CLOCK Gene rs3749474 as a Modulator of the Circadian Evening Carbohydrate Intake Impact on Nutritional Status in an Adult Sample.

Nutrients 2020 Apr 19;12(4). Epub 2020 Apr 19.

Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain.

The aim of this study was to evaluate the distribution of energy intake and macronutrients consumption throughout the day, and how its effect on nutritional status can be modulated by the presence of the rs3749474 polymorphism of the CLOCK gene in the Cantoblanco Platform for Nutritional Genomics ("GENYAL Platform"). This cross-sectional study was carried out on 898 volunteers between 18 and 69 years old (65.5% women). Anthropometric measurements, social issues and health, dietary, biochemical, genetic, and physical activity data were collected. Subsequently, 21 statistical interaction models were designed to predict the body mass index (BMI) considering seven dietary variables analyzed by three genetic models (adjusted by age, sex, and physical activity). The average BMI was 26.9 ± 4.65 kg/m, 62.14% presented an excess weight (BMI > 25 kg/m). A significant interaction was observed between the presence of the rs3749474 polymorphism and the evening carbohydrate intake (% of the total daily energy intake [%TEI]) (adjusted = 0.046), when predicting the BMI. Participants carrying TT/CT genotype showed a positive association between the evening carbohydrate intake (%TEI) and BMI (β = 0.3379, 95% CI = (0.1689,0.5080)) and (β = 0.1529, 95% CI = (-0.0164,0.3227)), respectively, whereas the wild type allele (CC) showed a negative association (β = -0.0321, 95% CI = (-0.1505,0.0862)). No significant interaction with the remaining model variables was identified. New dietary strategies may be implemented to schedule the circadian distribution of macronutrients according to the genotype. Clinical Trial number: NCT04067921.
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http://dx.doi.org/10.3390/nu12041142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231306PMC
April 2020

Physical fitness and physical activity association with cognitive function and quality of life: baseline cross-sectional analysis of the PREDIMED-Plus trial.

Sci Rep 2020 02 26;10(1):3472. Epub 2020 Feb 26.

Nutritional Genomics and Epigenomics Group, IMDEA Food, CEI UAM + CSIC, Madrid, Spain.

Physical activity (PA) has been hypothesized to be effective to maintaining cognitive function and delay cognitive decline in the elderly, but physical fitness (PF) could be a better predictor of cognitive function. We aimed to study the association between PA and PF with cognitive function and quality of life using cross-sectional data from 6874 participants of the PREDIMED-Plus trial (64.9 ± 4.9 years, 48.5% female). PF and PA were measured with a Chair Stand Test, the REGICOR and Rapid Assessment Physical Activity questionnaires. Cognitive function was measured with Mini-mental State Examination, Control Oral Word Association Test, Trail Making Test and Digit Span tests; whereas health-related quality of life was assessed with the SF36-HRQL test. Cognitive and quality of life scores were compared among PF quartiles and PA levels (low, moderate and high) with ANCOVA and with Chair Stand repetitions and energy expenditure from total PA with multivariable linear regression adjusted for confounding factors. PF associated with higher scores in phonemic and semantic verbal fluency tests and with lower TMT A time. However, PA was not associated with the neurocognitive parameters evaluated. Both PF and PA levels were strongly associated with a better quality of life. We concluded that PF, but not PA, is associated with a better cognitive function. This trial was retrospectively registered at the International Standard Randomized Controlled Trial (ISRCTN89898870, https://www.isrctn.com/ISRCTN89898870?q=ISRCTN89898870&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search) on 07/24/2014.
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http://dx.doi.org/10.1038/s41598-020-59458-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044289PMC
February 2020

Identification of Selective Inhibitors of N-Myristoyltransferase by High-Throughput Screening.

J Med Chem 2020 01 8;63(2):591-600. Epub 2020 Jan 8.

Center for Infectious Disease Research , Seattle , Washington 98109 , United States.

New drugs that target species, the causative agents of malaria, are needed. The enzyme -myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against () NMT. Hits were triaged based on potency and physicochemical properties and further tested against and () NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of NMT and serve as a starting point for subsequent medicinal chemistry efforts.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01343DOI Listing
January 2020

Identification of Small Molecules Disrupting the Ubiquitin Proteasome System in Malaria.

ACS Infect Dis 2019 12 7;5(12):2105-2117. Epub 2019 Nov 7.

Tres Cantos Medicines Development Campus, Diseases of the Developing World . GlaxoSmithKline , Severo Ochoa 2 , Tres Cantos , 28760 Madrid , Spain.

The ubiquitin proteasome system (UPS) is one of the main proteolytic pathways in eukaryotic cells, playing an essential role in key cellular processes such as cell cycling and signal transduction. Changes in some of the components of this pathway have been implicated in various conditions, including cancer and infectious diseases such as malaria. The success of therapies based on proteasome inhibitors has been shown in human clinical trials. In addition to its proven tractability, the essentiality of the UPS underlines its potential as a source of targets to identify new antimalarial treatments. Two assays, previously developed to quantify the parasite protein ubiquitylation levels in a high throughput format, have been used to identify compounds that inhibit parasite growth by targeting UPS. Among the positive hits, specific inhibitors of the proteasome have been identified and characterized. Hits identified using this approach may be used as starting points for development of new antimalarial drugs. They may also be used as tools to further understand proteasome function and to identify new targets in UPS.
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http://dx.doi.org/10.1021/acsinfecdis.9b00216DOI Listing
December 2019

Validation of the protein kinase CLK3 as a multistage cross-species malarial drug target.

Science 2019 08;365(6456)

Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK.

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the protein kinase CLK3, which we used in combination with chemogenetics to validate CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of CLK3 mediated rapid killing of asexual liver- and blood-stage and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against and Hence, our data establish CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.
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http://dx.doi.org/10.1126/science.aau1682DOI Listing
August 2019

rs780094 Polymorphism as A Genetic Variant Involved in Physical Exercise.

Genes (Basel) 2019 07 28;10(8). Epub 2019 Jul 28.

Nutrition and Clinical Trials Unit, IMDEA Food CEI UAM + CSIC, 28049 Madrid, Spain.

Exercise performance is influenced by genetics. However, there is a lack of knowledge about the role played by genetic variability in the frequency of physical exercise practice. The objective was to identify genetic variants that modulate the commitment of people to perform physical exercise and to detect those subjects with a lower frequency practice. A total of 451 subjects were genotyped for 64 genetic variants related to inflammation, circadian rhythms, vascular function as well as energy, lipid and carbohydrate metabolism. Physical exercise frequency question and a Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ) were used to qualitatively and quantitatively measure the average amount of physical exercise. Dietary intake and energy expenditure due to physical activity were also studied. Differences between genotypes were analyzed using linear and logistic models adjusted for Bonferroni. A significant association between rs780094 and the times the individuals performed physical exercise was observed ( = 0.004). The carriers of the minor allele showed a greater frequency of physical exercise in comparison to the major homozygous genotype carriers (OR: 1.86, 95% CI: 1.36-2.56). The analysis of the rs780094 variant suggests a possible association with the subjects that present lower frequency of physical exercise. Nevertheless, future studies are needed to confirm these findings.
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http://dx.doi.org/10.3390/genes10080570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722860PMC
July 2019

Inhibiting the stringent response blocks entry into quiescence and reduces persistence.

Sci Adv 2019 03 20;5(3):eaav2104. Epub 2019 Mar 20.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The stringent response enables () to shut down its replication and metabolism under various stresses. Here we show that lacking the stringent response enzyme Rel was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved -deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of Rel and showed that the lead compound X9 was able to directly kill nutrient-starved and enhanced the killing activity of isoniazid. Inhibition of Rel is a promising approach to target persisters, with the potential to shorten the duration of TB treatment.
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http://dx.doi.org/10.1126/sciadv.aav2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426458PMC
March 2019

Development of high throughput screening methods for inhibitors of ClpC1P1P2 from Mycobacteria tuberculosis.

Anal Biochem 2019 02 10;567:30-37. Epub 2018 Dec 10.

Department Cell Biology, Harvard Medical School, USA.

Tuberculosis affects about 100 million people worldwide and causes nearly 2 million deaths annually. It has been estimated that one third of all humans is infected with latent Mycobacterium tuberculosis (Mtb). Moreover, Mtb has become increasingly resistant to available antibiotics. Consequently, it is important to identify and characterize new therapeutic targets in Mtb and to synthesize selective inhibitors. ClpP1, ClpP2 and their associated regulatory ATPases, ClpX and ClpC1 are required for the growth of Mtb and for its virulence during murine infection and are highly attractive drug targets, especially since they are not present in the cytosol of mammalian cells, and they differ markedly from the mitochondrial ClpP complex. The importance of these proteins in Mtb is emphasized by the existence of several natural antibiotics targeting this system. In order to find new inhibitors of ClpC1P1P2 system, we developed an assay based on the ATP-dependent degradation of a fluorescent protein substrate. The hits obtained were further characterized with a set of secondary assays to identify precise targets within a complex. A large library of compounds was screened and led to the identification of a ClpC1 ATPase inhibitor demonstrating that this approach can be used in future searches for anti-TB agents.
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http://dx.doi.org/10.1016/j.ab.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484444PMC
February 2019

Association of calcium and dairy product consumption with childhood obesity and the presence of a Brain Derived Neurotropic Factor-Antisense (BDNF-AS) polymorphism.

Clin Nutr 2019 12 20;38(6):2616-2622. Epub 2018 Nov 20.

IMDEA-Food. CEI UAM+CSIC, Pabellón Central del Antiguo Hospital de Cantoblanco (Edificio nº 7), Crta. de Cantoblanco nº 8, 28049 Madrid, Spain. Electronic address:

Background & Aims: Calcium and dairy products have multiple health benefits. The objective of this work was to evaluate the association between calcium/dairy intake, blood pressure, the BDNF-AS rs925946 polymorphism and nutritional status in a group of schoolchildren.

Methods: As part of the GENYAL study to childhood obesity prevention, 221 children belonging to different areas of the Community of Madrid were enrolled. Anthropometric and dietary data were collected, and children were genotyped according to the rs925946 polymorphism. Adjusted logistic and linear models were used to describe the data.

Results: A significantly lower consumption of calcium in overweight versus normal weight children was observed (811.0 ± 174.1; 859.0 ± 195.9; 954.0 ± 223.1 mg; for obesity, overweight and normal weight, respectively, p = 0.010). Moreover, an inverse association between blood pressures and calcium intake was detected (β = -0.006 (-0.011, -3e)), p = 0.040. The number of dairy servings/day showed a protective effect against overweight (OR = 0.48 (0.29, 0.75), p = 0.001). Finally, common homozygous children (GG) showed an inverse association between the calcium intake and the BMI (β = -0.003 (-0.006, -0.001), p = 0.004), which was not observed in children carrying the T allele (β = -1.3e (-0.0022, 0.0024), p = 0.93).

Conclusion: Calcium and dairy were strongly associated with the nutritional status and blood pressure. The identification of differential effects of calcium/dairy consumption on the nutritional status according to genetics may contribute to the personalization of future nutritional advice.

Trial Registration: This study is registered at www.clinicaltrials.govNCT03419520.
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http://dx.doi.org/10.1016/j.clnu.2018.11.005DOI Listing
December 2019

Predicting transmission blocking potential of anti-malarial compounds in the Mosquito Feeding Assay using Plasmodium falciparum Male Gamete Inhibition Assay.

Sci Rep 2018 05 17;8(1):7764. Epub 2018 May 17.

Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.

Plasmodium falciparum Standard Membrane Feeding Assay (PfSMFA) is the current gold standard mosquito based confirmatory transmission blocking (TrB) assay for human malaria. However, owing to its complexity only selected gametocytocidal molecules are progressed into SMFA. Predictive tools for evaluation of TrB behavior of compounds in SMFA would be extremely beneficial, but lack of substantially large data sets from many mosquito feeds preempts the ability to perform correlations between outcomes from in vitro assays and SMFA. Here, a total of 44 different anti-malarial compounds were screened for inhibitory effect on male gamete formation in exflagellation inhibition assay (EIA) and the same drug-treated parasites were fed to mosquitoes in SMFA. Regression analysis was performed between outcomes of the two assays and regression models were applied to a randomly selected validation set of four compounds indicating no overfitting and good predictive power. In addition, the pIC50 for 11 different compounds obtained in the EIA was also correlated with pIC50's in SMFA. Resulting regression models provided pIC50 predictions in SMFA with reasonably good accuracy thereby demonstrating the use of a simple in vitro assay to predict TrB of molecules in a complex mosquito based assay.
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http://dx.doi.org/10.1038/s41598-018-26125-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958111PMC
May 2018

Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform.

Sci Rep 2018 03 2;8(1):3938. Epub 2018 Mar 2.

Department of Biosciences, Durham University, Stockton Road, Durham, DH1 3LE, UK.

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the world's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Drug discovery is a significant part of these efforts and here we describe the development and utilization of a novel assay to identify antiprotozoal inhibitors of the Leishmania enzyme, inositol phosphorylceramide (IPC) synthase. IPC synthase is a membrane-bound protein with multiple transmembrane domains, meaning that a conventional in vitro assay using purified protein in solution is highly challenging. Therefore, we utilized Saccharomyces cerevisiae as a vehicle to facilitate ultra-high throughput screening of 1.8 million compounds. Antileishmanial benzazepanes were identified and shown to inhibit the enzyme at nanomolar concentrations. Further chemistry produced a benzazepane that demonstrated potent and specific inhibition of IPC synthase in the Leishmania cell.
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http://dx.doi.org/10.1038/s41598-018-22063-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834442PMC
March 2018

High Throughput Screening Assay to Identify Modulators of IL-17 Expression.

Comb Chem High Throughput Screen 2017 ;20(9):804-819

GlaxoSmithKline Clinical Pharmacology Study Science and Operations, Stevenage, United Kingdom.

Objective: Herein we demonstrate the successful development of a new RORγt-enhanced IL-17F promoter-luciferase reporter assay and its use in a parallel high throughput screening approach, alongside a RORγt TR-FRET assay, to rapidly identify new small molecule RORγt/IL-17 inhibitors and evaluate their mode of action.

Material & Methods: We sought to identify cell-permeable small-molecule inhibitors of RORγt for rapid progression into hit-to-lead chemistry. As such, we developed the IL-17F promoter luciferase reporter assay in a stable human T-cell (Jurkat) line expressing the RORγt receptor and miniaturised it to a final volume of 8 µL in 1536 well plates for HTS use in screening a library of > 350k compounds. In parallel, a RORγt TR-FRET binding assay was employed to cross-screen the same set of compounds. This enabled the rapid identification of a small number of cell permeable RORγt antagonists showing promising activity in both assays and also highlighted a larger group of potentially very interesting hits which inhibited IL-17 reporter activity, but did not appear to modulate RORγt directly.

Result: A rigorous triaging process of the novel non-RORγt IL-17 antagonists was followed, making use of in-silico filtering, historical screening data, selectivity screening using an IL-2 reporter assay with an identical cellular background, and final profiling in a phenotypic PBMC IL-17A production assay. This resulted in the identification of a set of promising small molecule compounds which show IL-17 inhibition via potentially novel pathways.

Conclusion: This technique for the fast identification of cell-permeable IL-17 modulators acting through different mechanisms, highlights the benefits of adopting a parallel approach combining high throughput profiling of hits in multiple assay formats, with robust in-silico triaging.
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http://dx.doi.org/10.2174/1386207320666170602091308DOI Listing
January 2019

Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen.

Nat Commun 2017 05 17;8:15160. Epub 2017 May 17.

Diseases of the Developing World (DDW), GlaxoSmithKline, Madrid, Tres Cantos 28760, Spain.

Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.
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http://dx.doi.org/10.1038/ncomms15160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442318PMC
May 2017

Identification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis.

ACS Infect Dis 2015 Dec 22;1(12):580-5. Epub 2015 Jun 22.

DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.

Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.
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http://dx.doi.org/10.1021/acsinfecdis.5b00025DOI Listing
December 2015

Compound Prioritization in Single-Concentration Screening Data Using Ligand Efficiency Indexes.

J Chem Inf Model 2016 09 2;56(9):1705-13. Epub 2016 Sep 2.

Department of Computational Chemistry, Centro de Investigación Básica, GSK, Parque Tecnológico de Madrid , Tres Cantos 28760, Spain.

The triage of compounds at the single-concentration screening phase of high-throughput screening (HTS) requires multiobjective optimization in order to achieve the best selection of hits, both in terms of potency and physicochemical properties, for a given number of compounds to test. In this regard, ligand efficiency indexes, well established as guides for hit prioritization in the dose-response phase of HTS, are less studied in the single-concentration phase. In the present work the use of ligand efficiency indexes in the prioritization of compounds in single-concentration is investigated. Formulas for deriving them from single-concentration screening data are provided. The statistical association between the single-concentration and dose-response ligand efficiency indexes is evaluated with a wide historical data set including multiple screens of different target classes and screening technologies. The results show Pearson's correlation coefficients r above 0.9 for compounds with dose-response curves, and areas under the curve (AUC) of receiver operating characteristic (ROC) curves above 0.85 after including compounds with no dose-response curves. This good statistical association contains the contribution of both the physicochemical parameter(s) in the ligand efficiency indexes, as well as the biological activity, as demonstrated by permutation tests. The "cost/benefit" of using different thresholds of single-concentration ligand efficiency indexes in rescuing different numbers of efficient compounds is systematically investigated, and cost/benefit curves are provided. Approximate thresholds are proposed for the different ligand efficiency parameters that results in large percentages of efficient compounds rescued while attempting to reduce the cost of compounds to test in dose-response mode. Finally, a practical example of implementation of these indexes that considers clustering of compounds is described, where the rescue of efficient compounds is higher and with a much lower cost than a typical response-driven selection.
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http://dx.doi.org/10.1021/acs.jcim.6b00299DOI Listing
September 2016

Development of a Novel High-Density [3H]Hypoxanthine Scintillation Proximity Assay To Assess Plasmodium falciparum Growth.

Antimicrob Agents Chemother 2016 10 23;60(10):5949-56. Epub 2016 Sep 23.

Platform Technology and Science, Centro de Investigación Básica, GlaxoSmithKline, Tres Cantos, Spain.

The discovery and development of new antimalarial drugs are becoming imperative because of the spread of resistance to current clinical treatments. The lack of robustly validated antimalarial targets and the difficulties with the building in of whole-cell activity in screening hits are hampering target-based approaches. However, phenotypic screens of structurally diverse molecule libraries are offering new opportunities for the identification of novel antimalarials. Several methodologies can be used to determine the whole-cell in vitro potencies of antimalarial hits. The [(3)H]hypoxanthine incorporation assay is considered the "gold standard" assay for measurement of the activity of antimalarial compounds against intraerythrocytic forms of Plasmodium falciparum However, the method has important limitations, as the assay is not amenable for high-throughput screening since it remains associated with the 96-well plate format. We have overcome this drawback by adapting the [(3)H]hypoxanthine incorporation method to a 384-well high-density format by coupling a homogeneous scintillation proximity assay (SPA) and thus eliminating the limiting filtration step. This SPA has been validated using a diverse set of 1,000 molecules, including both a representative set from the Tres Cantos Antimalarial Set (TCAMS) of compounds and molecules inactive against whole cells. The results were compared with those from the P. falciparum lactate dehydrogenase whole-cell assay, another method that is well established as a surrogate for parasite growth and is amenable for high-throughput screening. The results obtained demonstrate that the SPA-based [(3)H]hypoxanthine incorporation assay is a suitable design that is adaptable to high-throughput antimalarial drug screening and that maintains the features, robustness, and reliability of the standard filtration hypoxanthine incorporation method.
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http://dx.doi.org/10.1128/AAC.00433-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038259PMC
October 2016

Identification of "Preferred" Human Kinase Inhibitors for Sleeping Sickness Lead Discovery. Are Some Kinases Better than Others for Inhibitor Repurposing?

ACS Infect Dis 2016 Mar 17;2(3):180-186. Epub 2016 Jan 17.

Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.

A kinase-targeting cell-based high-throughput screen (HTS) against was recently reported, and this screening set included the Published Kinase Inhibitor Set (PKIS). From the PKIS was identified 53 compounds with pEC ≥ 6. Utilizing the published data available for the PKIS, a statistical analysis of these active antiparasitic compounds was performed, allowing identification of a set of human kinases having inhibitors that show a high likelihood for blocking cellular proliferation in vitro. This observation was confirmed by testing other established inhibitors of these human kinases and by mining past screening campaigns at GlaxoSmithKline. Overall, although the parasite targets of action are not known, inhibitors of this set of human kinases displayed an enhanced hit rate relative to a random kinase-targeting HTS campaign, suggesting that repurposing efforts should focus primarily on inhibitors of these specific human kinases. We therefore term this statistical analysis-driven approach "".
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http://dx.doi.org/10.1021/acsinfecdis.5b00136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791575PMC
March 2016

Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF).

J Biomol Screen 2016 Jun 1;21(5):446-58. Epub 2016 Mar 1.

Molecular Discovery Research, Centro de Investigación Básica, GSK, Madrid, Spain

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine associated with multiple diseases, including neurodegenerative disorders. With the ultimate goal of providing novel chemotypes as starting points for development of disease-modifying therapeutics for neurodegeneration, we endeavored to screen the GSK compound collection for MIF inhibitors using a miniaturized, activity-based kinetic assay. The assay monitors the increase in absorbance at 320 nm resulting from keto-to-enol tautomerization of 4-hydroxyphenylpyruvate, a reaction catalyzed by MIF. We ran a full-diversity screen evaluating the inhibitory activity of 1.6 million compounds. Primary hits were confirmed and retested in an orthogonal assay measuring tautomerization of l-dopachrome methyl ester by the decrease in absorbance at 475 nm in kinetic mode. Selected compounds were progressed to medium-throughput mode-of-inhibition studies, which included time dependence, enzyme concentration dependence, and reversibility of their inhibitory effect. With these results and after inspection of the physicochemical properties of compounds, 17 chemotypes were prioritized and progressed to further stages of validation and characterization to better assess their therapeutic potential.
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http://dx.doi.org/10.1177/1087057116633997DOI Listing
June 2016

A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis.

ACS Infect Dis 2015 Dec 12;1(12):604-14. Epub 2015 Aug 12.

Center for Infectious Disease Research (Formerly Seattle Biomedical Research Institute) , Suite 500, Westlake Avenue North, Seattle, Washington 98109, United States.

Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy studies of tuberculosis, we paired knowledge and tools developed in academia with the infrastructure and chemistry resources of a large pharmaceutical company. Together we curated a focused library of 2508 potential antifolates, which were then tested for activity against live Mtb. We identified 210 primary hits, confirmed the on-target activity of potent compounds, and now report the identification and characterization of 5 hit compounds, representative of 5 different chemical scaffolds. These antifolates have potent activity against Mtb and represent good starting points for improvement that could lead to in vivo efficacy studies.
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http://dx.doi.org/10.1021/acsinfecdis.5b00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707675PMC
December 2015

Release of 50 new, drug-like compounds and their computational target predictions for open source anti-tubercular drug discovery.

PLoS One 2015 7;10(12):e0142293. Epub 2015 Dec 7.

Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142293PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671658PMC
June 2016