Biology subjects

Abdelrahman, S.

Publications and source records attributed to Abdelrahman, S..

4 recordsLinked to original sources

bioRxiv2025

Engineering Escherichia coli Nissle as safe chassis for delivery of therapeutic peptides

Synthetic biology enables the integration of sophisticated genetic programs into microorganisms, transforming them into potent vehicles for therapeutic applications. Engineering strategies for microorganisms are rapidly evolving, offering promising solutions for cancer therapy, microbiome modulation, digestive health support, and beyond. Developing novel tools to engineer safe, nonpathogenic microbial platforms is essential for advancing clinical therapies. In this work, we present an innovative engineering approach for the probiotic Escherichia coli Nissle (EcN), aimed at creating a safe and efficient chassis for the bioproduction of therapeutics. The EcN endogenous pM1 and pM2 plasmids were cured and re-engineered to introduce a CRISPR-Cas12 chromosome shredding device and a therapeutic-producing genetic circuit, thereby generating a nonproliferative therapeutic-delivery system. Next, we build an AI-based bioinformatic pipeline to predict Anticancer-Cell-Penetrating Peptides (ACCPP) candidates. As a proof-of-concept, a selected ACCPP was produced in the engineered EcN chromosome-shredded (CS) chassis. This strategy yields a robust and controllable platform for the safe production and delivery of therapeutics, paving the way for the future development of microbial therapies and their clinical applications. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/673081v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@2430d4org.highwire.dtl.DTLVardef@1ce2borg.highwire.dtl.DTLVardef@8686cdorg.highwire.dtl.DTLVardef@1fc23fb_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Discovery and Optimization of LAG-3-Targeted Small Molecules via DNA-Encoded Chemical Library (DEL) Screening for Cancer Immunotherapy

Lymphocyte activation gene-3 protein (LAG-3) is an immune checkpoint receptor that promotes T cell exhaustion and immune evasion in cancer. While antibody-based LAG-3 inhibitors have reached the clinic, small molecule modulators remain unexplored. Here, we report compound 11, the most potent small molecule LAG-3 inhibitor to date. Identified via a 4.2-billion compound DNA-encoded chemical library (DEL) screen, compound 11 binds LAG-3 with submicromolar affinity and disrupts the LAG-3/MHCII interaction. Molecular modeling suggests direct antagonism at the LAG-3/MHCII interface with potential allosteric effects. In functional assays, compound 11 enhances IFN-{gamma} secretion and promotes tumor cell killing in co-cultures of PBMCs and cancer cells. Importantly, compound 11 also exhibits favorable pharmacokinetics. These findings support the development of small molecule LAG-3 inhibitors as immunotherapeutic agents and provide a foundation for further optimization. Table of Contents artwork O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/668839v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@248c84org.highwire.dtl.DTLVardef@185510forg.highwire.dtl.DTLVardef@18cce50org.highwire.dtl.DTLVardef@13cfd8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Discovery of a First-in-Class SLIT2 Binder Disrupting the SLIT2/ROBO1 Axis via DNA-Encoded Library (DEL) Screening

The SLIT2/ROBO1 signaling axis plays a critical role in neural development, immune regulation, and tumor progression, including glioblastoma. However, small molecule inhibitors targeting this protein-protein interaction remain unexplored. Herein, we report the discovery and validation of DEL-S1, a first-in-class small molecule that binds to SLIT2 and disrupts its interaction with ROBO1. Using a DNA-encoded library (DEL) screen of 4.2 billion compounds, DEL-S1 was identified and confirmed to bind SLIT2 via temperature-related intensity change (TRIC) assay. Functional inhibition of the SLIT2/ROBO1 complex by DEL-S1 was demonstrated using a Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay, yielding an IC50 of 68.8 {+/-} 12.5 {micro}M. Molecular docking and molecular dynamics (MD) simulations revealed key interaction hotspots at the SLIT2 binding interface and confirmed that DEL-S1 impairs SLIT2/ROBO1 complex formation by inducing conformational rearrangements. DEL-S1 exhibited favorable ADME properties, including satisfactory plasma and microsomal stability, low cytotoxicity, and minimal hERG liability. To facilitate structure-activity relationship (SAR) exploration, we designed and implemented a modular, one-pot synthetic route leveraging cyanuric chloride reactivity, enabling rapid derivatization of the triazine scaffold of DEL-S1. This strategy yielded structurally diverse analogs, including water-soluble carboxylate derivatives with preserved SLIT2/ROBO1 inhibitory activity. Together, this work establishes a novel chemical scaffold targeting SLIT2 and introduces a flexible synthetic platform to support further optimization toward therapeutic development.

biochemistry↗

bioRxiv2022

Using Biometric Data to Measure and Predict Emotional Engagement of Video Games

Measurement and prediction of engagement in video games are very important because these are indicators to guide the development of game applications. Existing methods to predict game engagement are mostly based on subjective evaluations. This paper presents results correlating subjective and biometric data to show the potential of using biometric measures for assessment and prediction of engagement. Using three different games, we measured the biometric responses of participants and analyzed the responses using statistical and data mining methods. We compared the results with those obtained using subjective evaluations. Our results show that biometric measurements do correlate with subjective measures and better predict the self-reported engagement of a game.

bioinformatics↗