Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12.

COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12-metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.Communicated by Ramaswamy H. Sarma.

Nanovaccines in cancer immunotherapy: Focusing on dendritic cell targeting.

Cancer immunotherapy is proposed to eradicate tumors by stimulating host anti-tumor immunity through utilizing various therapeutic approaches. Cancer vaccines have become a promising approach for cancer immunotherapy among the proposed platforms, either alone or in combination with other therapeutic agents. Due to the suboptimal efficacy of cancer vaccines in clinical trials and the advent of nanotechnology in the biomedicine field, scientists developed nanoplatforms, such as various nanoparticles (NPs), cell-derived components, and nanocomplexes, to deliver vaccine components to target cells and tissues, thereby supporting their anti-tumor efficacy and minimizing adverse side effects. To increase the therapeutic effects of nanovaccines in cancer therapy, dendritic cell (DC) targeting through the modulation of the structure of the vaccines, such as using DC-specific ligands, has attracted extensive interest. Here, we reviewed the various forms of nanovaccines in cancer therapy and their therapeutic effects; we highlighted the properties and functions of DCs as the main antigen-presenting cells in immune responses and focused on targeting DCs in developing nanovaccines.

Targeted therapy of tumour microenvironment by gold nanoparticles as a new therapeutic approach.

Despite advances in cancer diagnosis and treatment, mortality associated with this malignant disease is still a major challenge in the health system. The tumour microenvironment (TME) provides a proper condition for cancer cells and gives rise to growth and metastasis. The TME is composed of fibroblasts, immune cells, extracellular matrix (ECM), endothelial cells, cytokines, and various factors; each of them has a special role in the process of tumour development. Therefore, the targeted treatment approach using gold nanoparticles (AuNPs) due to its unique properties, such as acceptable uptake, drug and ligand loading, low immunogenicity, high permeability, high cytotoxicity for tumour cells, and easy manipulation of particle properties; has had significant results in cancer treatment. In the current review study, we discussed more aspects of TME and associated targeted therapy methods with AuNPs.