Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy: Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of dystrophin protein. Elevating utrophin, a dystrophin paralog, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Professor Ghosh and team design and synthesise novel Quinazoline and quinoline-based small molecules as potent utrophin modulators, which are screened via high-throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of seventy molecules, upregulates utrophin 2.7 fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells brought from the Collaborative French Laboratory, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population. Pre-clinical and Clinical validation of this lead has already planned.

Advancing Antisense Oligonucleotide Delivery through Click Chemistry-Based Chemical Conjugation with Designed Short Non-Cationic Peptides for Duchenne Muscular Dystrophy: : Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disease caused by frame shift mutations in the gene encoding dystrophin. 2'-O-methyl phosphorothioate (2'-OMePS) serves as an antisense RNA platform clinically used in DMD patients to facilitate exon skipping and production of an internally truncated, yet functional dystrophin protein. Effective delivery and uptake of antisense oligonucleotides (ASOs) by target cells are crucial for their efficacy. Peptide-conjugated ASOs offer a promising next-generation platform, where a cell-penetrating peptide (CPP) is linked to the 2'-OMePS backbone to enhance cellular uptake. Herein, we designed and synthesized new non-cationic short CPP sequence that can be efficiently conjugated with the negatively charged 2'-OMePS ASO backbone using click chemistry. Conjugation of the lead peptide ETWWK to 2'-OMePS ASO resulted in significant cellular internalisation with precise nuclear localisation of the ASO cargo. Cellular uptake was assessed in C2C12 and human DMD patient-derived myoblast cells via fluorescence microscopy and flow cytometry. Our findings suggest that the identified peptide holds promise for facilitating ASO delivery at the site of splicing. This study highlights the efficient conjugation of CPPs to negatively charged 2'-OMePS ASO through tailored conjugation strategies, and will eventually be a therapeutic avenue for future ASO-based DMD treatments.

Discovery of gallic acid-based mitochondriotropic antioxidant attenuates LPS-induced neuroinflammation: This study reports the rational design and evaluation of a gallic acid-derived, mitochondria-targeted triazine antioxidant (Mito TBA 3) that mitigates oxidative stress-driven neuroinflammation. The authors synthesise a small library of TPP-tagged triazine conjugates, identify Mito TBA 3 as the most potent ROS/RNS scavenger through DPPH, ABTS, and CCA assays, and show that it is non-toxic and cytoprotective in neuronal cell models exposed to LPS or A beta, where it lowers intracellular and mitochondrial ROS, preserves mitochondrial morphology and membrane potential, and suppresses mitophagy and cytoskeletal disruption. Mechanistically, Mito TBA 3 downregulates TLR4-MyD88-NF-?B signaling, reduces pro-inflammatory cytokines, upregulates Nrf2-ARE-driven antioxidant genes, and limits the expression of apoptosis markers, indicating simultaneous anti-inflammatory and antioxidant actions. In an LPS-induced rat model, systemic administration of Mito TBA 3 crosses the blood-brain barrier, improves behavioral readouts of memory and mood, normalizes glial activation, preserves neuronal markers, and shows no detectable toxicity in major organs, outperforming aspirin as a reference anti-inflammatory agent.

Engineered Neuro-Regenerative Peptide Hydrogel for Directed Neural Lineage Reprograming and Regeneration of Sciatic Nerve Injury: Living systems are characterized by self-organisation, a principle underlying diverse pattern-forming processes ranging from geological structures to cellular and tissue architectures. Drawing inspiration from these natural design rules, we developed a nanofibrous, extracellular matrix-mimicking self-assembling peptide hydrogel. The hydrogel combines a neuroregenerative motif (NAP/NAV) derived from activity-dependent neuroprotective protein (ADNP) with a self-assembling sequence (K2[SL]6K2) to promote neurite extension. Notably, the material forms a network of aligned, filamentous structures that guide stem cell differentiation and directional neuronal alignment. To assess its therapeutic relevance, the hydrogel was evaluated in a rat sciatic nerve injury model, where guided regeneration is critical. Application of the hydrogel as a nerve guidance matrix resulted in enhanced structural repair and significant functional recovery within two weeks. These outcomes were supported by behavioral tests, histological findings, and gastrocnemius muscle reinnervation. Collectively, the results highlight the hydrogel's potential as an effective platform for peripheral nerve regeneration.

Discovery of powerful multifaceted antioxidant for combating oxidative stress associated with neurodegenerative disorders: Oxidative stress is a major contributor to neuronal damage in neurological disorders, necessitating effective antioxidant strategies for neuroprotection. In this study, we report the rational design of a potent multifunctional antioxidant small molecule (AOX) created by synergistically integrating epigallocatechin gallate (EGCG), gallic acid, and an 8-hydroxyquinoline moiety with metal-chelating properties. The designed molecule exhibits strong antioxidative, anti-apoptotic, and anti-inflammatory activities. Using hydrogen peroxide–induced oxidative stress in PC12-derived neurons, we demonstrate that AOX confers robust neuroprotection by preserving mitochondrial function and activating the Nrf2/ARE signaling pathway. Furthermore, AOX shows pronounced resistance to neuroinflammation in a transient bilateral common carotid artery occlusion (tBCCAO) ischemic stroke model, with minimal changes in glial activation markers including GFAP, IBA1, and S100. Collectively, these findings highlight AOX as a promising therapeutic candidate for protecting neurons against oxidative and inflammatory insults.

Discovery of imidazole-based GSK-3ß inhibitors for transdifferentiation of human mesenchymal stem cells to neurons: A potential single-molecule neurotherapeutic foresight: This study reports the discovery of SG 145C, an imidazole-based small molecule that functions as a single-component transdifferentiation trigger to convert human mesenchymal stem cells (hMSCs) into functional neurons. A focused imidazole library was built and computationally screened using 3D QSAR, docking, ADMET filtering, molecular dynamics, and DFT analysis to identify GSK 3-targeting candidates, from which SG 145C emerged as the best binder with favorable drug-like properties. In hMSCs, SG 145C is non cytotoxic and, at 5 µM for 7 days, induces robust neuronal morphology and expression of βIII tubulin, MAP2, NeuN, NF200, GAP43, SOX2, and NSE, while mesenchymal (CD44, CD73, vimentin) and astrocytic (GFAP) markers decline, without activating apoptosis or autophagy pathways. Mechanistic assays show that SG 145C directly inhibits GSK 3 activity, increases inactive pGSK 3(Ser9), stabilizes and upregulates β-catenin, and drives Wnt/β catenin-dependent transcription, as Wnt pathway blockade suppresses, and co-treatment with the GSK 3 inhibitor CHIR99021 enhances, neuronal gene induction. Patch clamp recordings confirm that SG 145C-derived cells fire action potentials and exhibit spontaneous electrical activity, establishing SG 145C as a first-in-class single small-molecule GSK 3 inhibitor capable of driving hMSC-to-neuron transdifferentiation with potential applications in neuroregeneration and disease modeling.

EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats: Aging and neurodegenerative disorders are associated with reduced adult neurogenesis and an accumulation of quiescent neural stem cells (NSCs), ultimately limiting the brain's regenerative potential. Current therapeutic approaches, including stem cell transplantation and neurodegeneration prevention, show limited success, highlighting the need for targeted strategies to restore NSC activity. In this study, we designed an EphA4 receptor-targeted peptide ligand using an in silico approach and chemically conjugated it to adipose tissue-derived extracellular vesicles (EVs) to generate an engineered system termed Exo-pep-11. The engineered EV selectively targets NSCs via EphA4 receptors, promoting NSC internalization, proliferation, and differentiation. Receptor specificity was confirmed by a ~2.3-fold reduction in uptake following EphA4 antibody blocking. Exo-pep-11 treatment enhanced NSC proliferation (~1.9-fold) and increased expression of Nestin and ID1. In aging rats, Exo-pep-11 significantly elevated neurogenesis markers TH and Tuj1 in the olfactory bulb. These findings position Exo-pep-11 as a promising strategy to counteract age-related declines in neurogenesis.

Amyloid-Inspired Engineered Multidomain Amphiphilic Injectable Peptide Hydrogel-An Excellent Antibacterial, Angiogenic, and Biocompatible Wound Healing Material: The ingrained mechanical robustness of amyloids in association with their fine-tunable physicochemical properties results in the rational design and synthesis of tailor-made biomaterials for specific applications. However, the incredible antimicrobial efficacy of these ensembles has largely been overlooked. This research work provides an insight into the interplay between self-assembly and antimicrobial activity of amyloid-derived peptide amphiphiles and thereby establishes a newfangled design principle toward the development of potent antimicrobial materials with superior wound healing efficacy. Apart from the relationship with many neurodegenerative diseases, amyloids are now considered as an important cornerstone of our innate immune response against pathogenic microbes. Impelled by this observation, a class of amphiphilic antimicrobial peptide-based biomaterial has been designed by taking Aβ42 as a template. The designed AMP due to its amphipathic nature undergoes rapid self-assembly to form a biocompatible supramolecular hydrogel network having significant antibacterial as well as wound healing effectivity on both Gram-negative P. aeruginosa and MRSA-infected diabetic wounds via reduced inflammatory response and enhanced angiogenesis. Results suggest that disease-forming amyloids can be used as a blueprint for the fabrication of biomaterial-based antimicrobial therapeutics by fine-tuning both the hydrophobicity of the β-aggregation prone zone as well as membrane interacting cationic residues.