Biology subjects

Abdo, A.

Publications and source records attributed to Abdo, A..

4 recordsLinked to original sources

bioRxiv2026

Cyclic Peptides Target CAPON and Modulate Cellular Responses under Alzheimers Disease-Relevant Stress

CAPON (NOS1AP) is an adaptor protein involved in neuronal nitric oxide synthase (nNOS) signaling and has been implicated in Alzheimers disease (AD), excitotoxicity, and tau-associated neurodegeneration. Here, we report the identification of cyclic peptide ligands targeting CAPON using phage display screening of a disulfide-constrained peptide library. Phage enrichment, ELISA validation, microscale thermophoresis (MST), and biolayer interferometry (BLI) identified CAP1 as the lead peptide, exhibiting low micromolar binding affinity toward CAPON. Computational studies further supported stable CAPON-CAP1 interactions through complementary hydrophobic and electrostatic contacts. Functionally, CAP1 attenuated A{beta}42-induced neuronal toxicity, suppressed NMDA-driven nitric oxide production, and reduced pathological tau phosphorylation in neuronal models under AD-relevant stress conditions. In addition, CAP1 demonstrated favorable preliminary pharmacokinetic properties, including good aqueous solubility, plasma stability, and measurable membrane permeability. Collectively, these findings establish the first cyclic peptide ligands targeting CAPON and identify CAP1 as a promising scaffold for modulation of CAPON-dependent neurodegenerative signaling.

pharmacology and toxicology↗

bioRxiv2026

Discovery of MA48, a Small Molecule Inhibitor of CAPON (NOS1AP)-NOS1 Protein-Protein Interaction

CAPON (also known as NOS1AP) is an adaptor protein of neuronal nitric oxide synthase (nNOS) that has been implicated in the progression of multiple neurodegenerative diseases, making it an attractive but largely unexplored therapeutic target. To identify small molecule CAPON modulators, we screened a library of 10,000 compounds for CAPON binding using affinity selection-mass spectrometry (AS-MS), which led to the identification of compound MA48 as a potential CAPON binder. Subsequent biophysical validation using microscale thermophoresis (MST) confirmed direct binding, with MA48 exhibiting a dissociation constant (Kd) of 11.9 {micro}M. Structure-activity relationship (SAR) analysis combined with molecular docking was performed to elucidate key pharmacophoric features underlying the MA48/CAPON interaction. To determine whether MA48 disrupts the CAPON-nNOS interaction in a cellular context, we conducted a NanoBRET assay, which demonstrated that MA48 significantly inhibited this interaction in living cells. Collectively, these findings suggest that MA48 represents the first reported small molecule inhibitor of CAPON and provides a foundation for further development of CAPON-targeted therapeutics.

biophysics↗

bioRxiv2026

Exploiting NMR Ensemble Heterogeneity Enables Small Molecule Discovery Against Dynamic Protein-Protein Interfaces

Protein-protein interactions governed by conformationally heterogeneous domains remain difficult to drug because ligand-competent states are often absent from single static structures. Here, we present AtlasNMR, a statistical framework that transforms multi-model NMR ensembles into screening-ready conformational hypotheses for small molecule discovery. Using the neuronal nitric oxide synthase (nNOS) PDZ domain that engages the adaptor protein CAPON (NOS1AP) as a model system, AtlasNMR identified two representative conformational states capturing the dominant and minor populations of the NMR ensemble. Ensemble-based virtual screening followed by consensus ranking yielded MC-3, a small molecule modulator that disrupts the NOS1-NOS1AP interaction in live cells and directly engages the nNOS PDZ domain. MC-3 produced convergent neuroprotective effects in disease-relevant neuronal models by reducing amyloid-{beta}-induced cytotoxicity, suppressing NMDA-driven nitrosative stress, and attenuating pathological tau phosphorylation, while exhibiting a balanced early lead-like ADME and safety profile. Together, this work establishes a generalizable strategy for exploiting NMR ensemble heterogeneity to enable small molecule discovery against dynamic protein-protein interfaces.

pharmacology and toxicology↗

bioRxiv2025

Identification of a First-In-Class Small Molecule CAPON Binder Using Affinity Selection-Mass Spectrometry Screening

NOS1AP (CAPON) is an adaptor protein of neuronal nitric oxide synthase (nNOS) correlated with Alzheimers disease progression, making it an attractive yet unexplored therapeutic target. To assess its chemical tractability, we employed affinity selection-mass spectrometry (AS-MS) to screen approximately 10,000 small molecules for CAPON binding, identifying 52 initial hits. These compounds were further evaluated for true binding interactions and potential autofluorescence or quenching effects using the Dianthus platform. Five compounds were selected for quantitative affinity determination by microscale thermophoresis (MST). Among these, compound MA32 exhibited a dissociation constant (Kd) of 74 M. MA32 thus represents the first AS-MS-identified small-molecule binder of CAPON. This study establishes a workflow for small-molecule discovery against novel, previously uncharacterized targets.

biophysics↗