Correction to "Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection".

[This corrects the article DOI: 10.1021/acsomega.3c02921.].

Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection.

The urgency to find complementary therapies to current SARS-CoV-2 vaccines, whose effectiveness is preserved over time and not compromised by the emergence of new and emerging variants, has become a critical health challenge. We investigate the possibility of jamming the opening of the Receptor Binding Domain (RBD) of the spike protein of SARS-CoV-2 with small compounds. Through in silico screening, we identified two potential candidates that would lock the Receptor Binding Domain (RBD) in a closed configuration, preventing the virus from infecting the host cells. We show that two drugs already approved by the FDA, mithramycin and dihydroergotamine, can block infection using concentrations in the µM range in cell-based assays. Further STD-NMR experiments support dihydroergotamine's direct interaction with the spike protein. Overall, our results indicate that repurposing of these compounds might lead to potential clinical drug candidates for the treatment of SARS-CoV-2 infection.

Topical systems for the controlled release of antineoplastic Drugs: Oxidized Alginate-Gelatin Hydrogel/Unilamellar vesicles.

The efficacy of chemotherapeutic procedures relies on delivering proper concentrations of anti-cancer drugs in the tumor surroundings, so as to prevent potential side effects on healthy tissues. Novel drug carrier platforms should not just be able to deliver anticancer molecules, but also allow for adjustements in the way these drugs are administered to the patients. We developed a system for delivering water-insoluble drugs, based on the use of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or bis(2-ethylhexyl) sulfosuccinate benzyl-n-hexadecyldimethylammonium (BHD-AOT), embedded into oxidized alginate-gelatin (ADA/Gel) hydrogel, emulating a patch for topic applications. After being loaded with curcumin, cancer cells such as human colorectal adenocarcinoma (HCT116 and DLD-1) and melanoma cell lines (MEL501), and non-malignant cells such as mammary epithelial cell lines (NMuMG) and embryonal fibroblasts (NIH 3T3 or NEO cells) were analyzed for biocompatibility and cytotoxic effects. The results show that the proposed system can load comparatively higher concentrations of the drug (with respect to other nano/microcarriers in the literature), and that it can enhance the likelihood of the drug being uptaken by cancer cells instead of non-malignant cells. These assays were complemented by diffusion studies across the stratum corneum of rat skin, with the aim of determining the system's efficiency during topical application. Finally, the stability of the patch was tested after lyophilization to determine its potential pharmaceutical use. As a whole, the combined system represents a highly reliable and robust method for embedding and delivering complex insoluble chemotherapeutical molecules, and it is less invasive than other alternative methods in the literature.

Assessing the Mobility of Severe Acute Respiratory Syndrome Coronavirus-2 Spike Protein Glycans by Structural and Computational Methods.

Two years after its emergence, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several vaccines. The extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin converting enzyme 2 (ACE2) through its receptor binding domain (RBD), is the major target of neutralizing antibodies. Like to many other viral fusion proteins, the SARS-CoV-2 spike protein utilizes a glycan shield to thwart the host immune response. To grasp the influence of chemical signatures on carbohydrate mobility and reconcile the cryo-EM density of specific glycans we combined our cryo-EM map of the S ectodomain to 4.1 Å resolution, reconstructed from a limited number of particles, and all-atom molecular dynamics simulations. Chemical modifications modeled on representative glycans (defucosylation, sialylation and addition of terminal LacNAc units) show no significant influence on either protein shielding or glycan flexibility. By estimating at selected sites the local correlation between the full density map and atomic model-based maps derived from molecular dynamics simulations, we provide insight into the geometries of the α-Man-(1→3)-[α-Man-(1→6)-]-ß-Man-(1→4)-ß-GlcNAc(1→4)-ß-GlcNAc core common to all N-glycosylation sites.

Catanionic nanocarriers as a potential vehicle for insulin delivery.

Diabetes is a disease that affects millions of people in the World, constituting a global problem. Patients are administered insulin subcutaneous injections, resulting in high costs and frequent infections in the injection site. A possible solution to this problem may be the use of nanotechnology. Nanotransporters can act as specific release systems able to overcome the current limitations to drug delivery. Liposomes and vesicles can deliver drugs directly and efficiently to the site of action, decreasing toxicity and adverse effects. In previous studies, we demonstrated the biocompatibility and safety of catanionic benzyl n-hexadecyldimethylammonium 1,4 -bis-2-ethylhexylsulfosuccinate (BHD-AOT) vesicles using both in vitro and in vivo tests. Thus, the aims of this work were to evaluate the ability of the BHD-AOT vesicles to encapsulate insulin; to analyze the structural properties and stability of the system, vesicle-Insulin (VIn), at different pH conditions; and to study the ability of VIn to decrease the glycemia in miceby different administration routes. Our results showed that 2 and 5 mg mL-1 of vesicles were able to encapsulate about 55 % and 73 % of insulin, respectively. The system VIn showed a significant increase in size from 120 to 350 nm, changes in the surface zeta potential value, and high stability to different pH conditions. A significant decrease of the glycemia after VIn administration was demonstrated in in vivo assays, including the oral route. Our results reveal that BHD-AOT vesicles may be an appropriate system to encapsulate and protect insulin, and may be a potential system to be administrated in different ways as an alternative strategy to conventional therapy.