Apart from ATP generation, mitochondria are involved in a wide range of functions, making them one of the most prominent organelles of the human cell. Mitochondrial dysfunction is involved in the pathophysiology of several diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. This makes it a target for a variety of therapeutics for the diagnosis and treatment of these diseases. The use of nanoparticles to target mitochondria has significant importance in modern times because they provide promising ways to deliver drug payloads to the mitochondria by overcoming challenges, such as low solubility and poor bioavailability, and also resolve the issues of the poor biodistribution of drugs and pharmacokinetics with increased specificity. This review assesses nanoparticle-based drug-delivery systems, such as liposomes, DQAsome, MITO-Porters, micelles, polymeric and metal nanocarriers, as well as quantum dots, as mitochondria-targeted strategies and discusses them as a treatment for mitochondrial disorders.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rampant worldwide and is a deadly disease for humans. Our current work emphasizes on molecular dynamics simulation (MDS) targeting nuclear factor-kappa B (NF-κB), the well-known human transcription factor controlling innate and adaptive immunity, to understand its mechanism of action during COVID-19 in humans. NF-κB was interacted with the SARS-CoV-2 spike protein in an in silico MDS experiment, revealing the NF-κB site at which the SARS-CoV-2 spike protein interacts. We screened some known drugs via docking studies on NF-κB used as a receptor. The MDS software Schrodinger generated more than 2000 complexes from these compounds and using the SMILES format of these complexes, 243 structures were extracted and 411 conformers were generated. The drug used as a ligand that docked with NF-κB with the best docking score and binding affinity was Sulindac sodium as its trade name. Furthermore, RMSF data of sulindac sodium and NF-κB displayed minimal fluctuations in the protein structures, and the protein-ligand complex had reduced flexibility. Sulindac sodium is hence suggested as a suitable drug candidate for repurposing in clinical trials for SARS-CoV-2 infections. This drug potently blocked the spike protein’s interaction with NF-κB by inducing a conformational change in the latter. Arguably, NF-κB inaction is desired to have normal immunity and can possibly be retained using proposed drug. This work provides a significant lead for drug repurposing to combat SARS-CoV-2 and its various mutant forms and reveals new approach for controlling SARS-CoV-2-induced disease.

The authors state that they adhere with COPE guidelines on publishing ethics as described elsewhere at https://publicationethics.org/. The authors also undertake that they are not associated with any other third party (governmental or non-governmental agencies) linking with any form of unethical issues connecting to this publication. The authors also declare that they are not withholding any information that is misleading to the publisher in regard to this article.

No abstract

COVID19 caused due to SARS-CoV2, is rampant world wide and human beings with previous history of other major ailments are increasingly at risk of mortality due to this disease in a predetermined manner. Countries have developed vaccines claiming to counter the SARS-CoV2 virus to a great extent. However, convincing evidences are lacking in this regard as mortality post-vaccination is not uncommon, though exact reason of the morbidity is unknown yet. Our current work primarily focuses on molecular dynamics simulation (MDS) targeting NF-kappa B (NF-κB), the well-known human transcription factor that controls innate and adaptive immunity, with an aim to understand its mechanism of action under COVID19 virus load in humans. To understand this, NF-κB was made to interact with spike protein of SARS-CoV2 in an in silico experimental design employing Molecular Dynamics Simulation (MDS) studies. Some interesting findings were made revealing the site of NF-κB at which spike protein of SARS-CoV2 interacts. We attempted to subject some known drugs to be screened based on their docking studies with nuclear factor kappa B (NF-κB) to MDS studies. MDS Software Schrodinger generated more than 2000 complexes from these compounds and structure exportation was hence not possible. Using the SMILE IDs of 243 ligands, we generated a total of 411 confirmers employing the ligand preparation wizard. These were docked at the active site using the Glide program. A drug named Sulindac sodium (Molecular Formula C20H16FO3S) was found having ability to target NF-κB and can be repurposed for controlling SARS-CoV2 based on the positive results obtained during MDS analysis. This drug showed potency to block the spike protein’s interaction with NF-κB by bringing about a conformational change in the latter. It is hypothesized presently that NF-κB activation that leads to migration of this molecule to nucleus for gene transcription and immunity inhibition, is triggered either directly by binding of spike protein to NF-κB or spike protein’s interaction with some pathway kinase that phosphorylates IκBs, another molecule essential to get released from the NF-κB-IκB complex, to set NF-κB free to get translocated to nucleus for action. Arguably, NF-κB inaction is desired to allow normal immunity to become functional and can possibly be retained using our repurposed drug-based interaction. This work provides a significant lead in the knowledge on drug development for tackling SARS-CoV2 and its various mutant forms by blocking the functioning of the virus in a NF-κB-dependent manner in host tissues and opens up new vistas in controlling critical state SARS-CoV2 disease.