Biology subjects

Cherkaoui, M.

Publications and source records attributed to Cherkaoui, M..

5 recordsLinked to original sources

bioRxiv2024

Applications of some artificial intelligence tools in the drug design of some compounds targeting the main viral protease of the Feline Infectious Peritonitis Virus (FIPV) in cats

Feline infectious peritonitis virus (FIPV) is one of cats most serious viral infections. The FIPV infection induces a complicated syndrome in the affected cats, including immunosuppression and severe inflammatory conditions. Unfortunately, these vaccines cannot prevent cats from getting infected with these viral infections. There is ongoing research on preparing antiviral therapies against FIPV in cats. However, these are still in clinical trials and have not been fully approved by the drug authorities in many countries, including the USA. Targeting the main viral proteases is one of the promising trends in the drug design of many viral diseases, including coronaviruses. The main goal of the current study was to repurpose and test the efficacy of some known antiviral drugs to treat FIPV infection in cats by targeting the FIPV-main protease enzyme. To achieve these goals, we used the in-silico prediction and molecular docking tools to screen and identify some drugs targeting FIPV-MPro. We used the docking and binding energies as the main parameters for selecting target compounds (FIPV-MPro). Our results show that out of the 15 antiviral and immunomodulatory compounds, the top-ranked inhibitors for the FIPV-Mpro are (Michael acceptor inhibitors (N3), Sofosbuvir, and methotrexate).In conclusion, our results confirmed the potential applications of the predicted FIPV-Mpro inhibitors either independently or in combination with other immune-modulatory compounds. Further in vitro and in vivo studies are encouraged to test the efficacy of these identified compounds as potent inhibitors for the MPro of the FIPV in cats. This study will pave the way for the development of novel drugs that treat FIPV infection in cats.

microbiology↗

bioRxiv2023

Fast alignment of mass spectra in large proteomics datasets, capturing dissimilarities arising from multiple complex modifications of peptides

BackgroundIn proteomics, the interpretation of mass spectra representing peptides carrying multiple complex modifications is still challenging, currently limited by the number of potential modifications considered in a single analysis and the need to know them in advance. Further developments must be done in the field to help the scientific community to discover new post-translational modifications that play an essential role in disease and to understand how chemical modifications carried by food proteins could impact our health. ResultsTo make progress on this issue, we implemented SpecGlobX (SpecGlob eXTended to eXperimental spectra), a standalone Java application that quickly determines the best spectral alignments of a (possibly very large) list of Peptide-to-Spectrum Matches (PSMs) provided by any open modification search method, or generated by the user. As input, SpecGlobX reads a file containing spectra in MGF or mzML format and a semicolon-delimited spreadsheet describing the PSMs. As output, SpecGlobX returns the best alignment for each PSM, splitting the mass difference between the spectrum and the peptide into one or more shifts while considering the possibility of non-aligned masses (a phenomenon resulting from many situations including neutral losses). SpecGlobX is fast, able to align one million PSMs in about 1.5 minutes on a standard desktop. Firstly, we remind the foundations of the algorithm and detail how we adapted SpecGlob (the method we previously developed following the same aim, but limited to the interpretation of perfect simulated spectra) to the interpretation of imperfect experimental spectra. Then, we highlight the interest of SpecGlobX as a complementary tool downstream to three open modification search methods on a large simulated spectra dataset. Finally, we show on a smaller dataset that SpecGlobX performs equally well on experimental and simulated spectra. ConclusionsSpecGlobX is helpful as a decision support tool, providing keys to interpret peptides carrying complex modifications still poorly considered by current open modification search software. Better alignment of PSMs enhances confidence in the identification of spectra provided by open modification search methods and should improve the interpretation rate of spectra.

bioinformatics↗

bioRxiv2021

The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

While viral infections are known to hijack the transcription and translation of the host cell, the extent to which encoded viral proteins coordinate these perturbations remains unclear. Here we demonstrate that the oncoviral proteins Tax and HBZ interact with specific components of the spliceosome machinery, including the U2 auxiliary factor large subunit (U2AF2), and the complementary factor for APOBEC-1 (A1CF), respectively. Tax and HBZ perturb the splicing landscape in T-cells by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia (ATL) patients, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinately used by Tax and HBZ to reprogram the transcriptome. HighlightsO_LITax and HBZ interact with RNA-binding proteins as well as transcription factors C_LIO_LIHTLV-1 encoded proteins Tax and HBZ alter the splicing landscape in T-cells C_LIO_LITax and HBZ expression affect alternative splicing of 33 and 63 cancer genes, respectively C_LIO_LIOpposing roles for Tax and HBZ in deregulation of gene expression C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/427104v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5f6f0org.highwire.dtl.DTLVardef@6725b3org.highwire.dtl.DTLVardef@1dc32fborg.highwire.dtl.DTLVardef@19728c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

Seeking an optimal dosing regimen for OZ439-DSM265 combination therapy for treating uncomplicated falciparum malaria

The efficacy of Artemisinin-based Combination Therapies (ACTs), the first- line treatments of uncomplicated falciparum malaria, has been declining in malaria endemic countries due to the emergence of malaria parasites resistant to these com- pounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model that accounts for the pharmacodynamic interaction between the two drugs. Model parameters were estimated using data from healthy volunteers infected with falciparum malaria collected from four trials: three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439-DSM265. Posterior predictive simulations of the model were performed to determine efficacious dosing regimens. One such regimen that predicted at least 90% of infected individuals cured 42 days after the administration of the drugs, while within the tolerable dose range, is 800 mg of OZ439 and 450 mg of DSM265. Our model can be used to inform future phase 2 and 3 clinical trials of OZ439-DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing.

pharmacology and toxicology↗

bioRxiv2018

Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe

European populations display low genetic diversity as the result of long term blending of the small number of ancient founding ancestries. However it is still unclear how the combination of ancient ancestries related to early European foragers, Neolithic farmers and Bronze Age nomadic pastoralists can fully explain genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the overall continental diversity, but to date have been systematically understudied. Here we characterised the ancestry profiles of modern-day Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe and the rest of the world. Italian genomes captured several ancient signatures, including a non-steppe related substantial ancestry contribution ultimately from the Caucasus. Differences in ancestry composition as the result of migration and admixture generated in Italy the largest degree of population structure detected so far in the continent and shaped the amount of Neanderthal DNA present in modern-day populations.\n\nOne sentence summaryAncient and historical admixture events shaped the genetic structure of modern-day Italians, the ancestry profile of Southern European populations and the continental distribution of Neanderthal legacy.

genomics↗