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The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir’s potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.

The SARS-CoV-2 E protein through its C-terminal PDZ-binding motif (PBM) interacts with several host PDZ-containing proteins, including Zonula occludens-1 (ZO-1) protein via its PDZ2 domain, thereby contributing to viral pathogenesis. Targeting this interaction represents a potential therapeutic strategy. In this study, we determined the X-ray structure of the E PBM peptide in complex with the ZO-1 PDZ2 domain at 1.7 Å resolution. The structure revealed a domain-swapped dimer conformation of ZO-1 PDZ2, with the E PBM peptide conventionally bound within the PDZ domain’s canonical binding groove, exhibiting key interactions characteristic of type II PBM/PDZ interactions. To identify potential inhibitors of the E PBM/ZO-1 PDZ2 interaction, we performed a Homogeneous Time-Resolved Fluorescence (HTRF) screening using a protein-protein interaction-focused library of 1000 compounds. This led to the identification of 36 hits that disrupted this interaction. Subsequent cytotoxicity and dose-response assays narrowed the selection to 14 promising compounds. Docking simulations showed that some compounds bind within or near the PBM-binding pocket, supporting a competitive mechanism of interaction inhibition, while others bind at a central interface between the two PDZ monomers, suggesting an inhibition of dimerization, which in turn prevents PBM binding. Thus, the E PBM/ZO-1 PDZ2 interaction can be inhibited through both direct and indirect mechanisms. Finally, antiviral assays using a NanoLuciferase-expressing recombinant SARS-CoV-2 demonstrated that one compound, C19, significantly reduced viral replication, highlighting its potential as a candidate for further therapeutic development.

Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA.Boutary et al. describe siRNA based therapy conjugated with squalene nanoparticles as an efficient approach to normalize PMP22 protein levels, restore locomotor activity, electrophysiological parameters and function of myelin sheath in CMT1A mouse models. These findings could be useful to develop therapeutic strategies for inherited peripheral neuropathies.

Background/Aim: Rhenium(I)-diselenoether (Re-diSe) is a drug under development for the treatment of metastatic cancers, with selective inhibitory effects on MDA-MB231 cancer cells compared to normal HEK-293 cells, and with greater effects than its diselenide (di-Se) ligand. Rhenium (Re) compounds inhibit cathepsins, which are important proteolytic enzymes in cancer. This study investigated the effects of Re-diSe and di-Se on the production of cathepsins B and S in MDA-MB231 malignant and HEK-293 normal cells and their inhibitory effects following treatment with different doses for 72 h. Materials and Methods: Elisa tests were used to assay the amount of cathepsins B and S in the medium of cultures. Results: Re-diSe, but not diSe affected the viability of malignant cells and the expression of cathepsins B and S. Conclusion: To the best of our knowledge, this is the first demonstration that Re-diSe may decrease the production of cathepsins B and S in cancer cells at doses as low as 10 μM.

Nanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)-palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low temperature in water without any organic co-solvent. Combined with an improved one-step synthesis of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of 4′-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional group tolerance.

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo. [Display omitted] We have demonstrated that the squalene derivative of the anticancer agent gemcitabine (SQGem) is capable of strongly interacting with the LDLs. This interaction enabled the preferential accumulation of the SQGem in MDA-MB-231 breast cancer cells with high LDL receptor expression and led to improved pharmacological activity in tumor-bearing mice.

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene. The systemic circulation time of adenosine is prolonged by forming nanoassemblies with squalene, and this can improve neurologic recovery in mice affected by a stroke or spinal cord injury.

TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene.

The “Golden era” of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55–63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells.

For several decades, various peptides have been under investigation to prevent ischemia/reperfusion (I/R) injury, including cyclosporin A (CsA) and Elamipretide. Therapeutic peptides are currently gaining momentum as they have many advantages over small molecules, such as better selectivity and lower toxicity. However, their rapid degradation in the bloodstream is a major drawback that limits their clinical use, due to their low concentration at the site of action. To overcome these limitations, we have developed new bioconjugates of Elamipretide by covalent coupling with polyisoprenoid lipids, such as squalenic acid or solanesol, embedding self-assembling ability. The resulting bioconjugates were co-nanoprecipitated with CsA squalene bioconjugate to form Elamipretide decorated nanoparticles (NPs). The subsequent composite NPs were characterized with respect to mean diameter, zeta potential, and surface composition by Dynamic Light Scattering (DLS), Cryogenic Transmission Electron Microscopy (CryoTEM) and X-ray Photoelectron Spectrometry (XPS). Further, these multidrug NPs were found to have less than 20% cytotoxicity on two cardiac cell lines even at high concentrations, while maintaining an antioxidant capacity. These multidrug NPs could be considered for further investigations as an approach to target two important pathways involved in the development of cardiac I/R lesions.