Vandetanib for COVID-19

Background: Vandetanib is a clinically approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of medullary thyroid cancer. Recent studies have also suggested potential activity against the SARS-CoV-2 main protease (Mpro), indicating dual therapeutic relevance. However, its clinical use is limited by photosensitivity side effects, the molecular basis of which remains poorly understood. This study aims to elucidate the conformational, spectroscopic, and electronic properties of vandetanib underlying its photoreactivity. Methods: Density functional theory (DFT) was employed to explore vandetanib’s conformational landscape, electronic structure, and spectroscopic behavior. Low-energy conformers were identified and compared with experimental crystal and NMR data. Time-dependent DFT (TD-DFT) calculations were used to simulate UV–Vis absorption spectra and assign key electronic transitions. Results: Eight low-energy conformer clusters, including the global minimum structure, were identified. The global minimum was validated by consistency with crystal and experimental NMR data, emphasizing the role of conformational averaging. TD-DFT simulations successfully reproduced the two main UV–Vis absorption bands, with the primary band (~339 nm) assigned to a HOMO–1 → LUMO charge-transfer excitation between the N-methyl piperidine and quinazoline rings, pinpointing a structural contributor to photoreactivity. Additionally, the N-methyl piperidine ring was identified as a major metabolic hotspot, undergoing multiple biotransformations potentially linked to phototoxicity. Conclusions: This study provides molecular-level insights into the structural and photophysical origins of vandetanib’s photosensitivity. The findings improve understanding of its adverse effects and can inform the safer design of EGFR-targeting drugs with reduced phototoxic risks.

Abstract Background Viruses such as Ebola, Marburg, influenza, mpox, MERS-CoV, SARS-CoV, and SARS-CoV-2 pose a significant risk for future pandemics. Developing novel antiviral medicines can be time-consuming and resource intensive. Repurposing existing medicines with antiviral activity offers a faster, cost-effective strategy to expand treatment options during public health emergencies. This scan aimed to identify and synthesise recent evidence on repurposed antiviral medicines under investigation for these viruses. Method A horizon scanning approach was employed, starting with a targeted search in Embase, followed by a systematic search of ClinicalTrials.gov to capture the developmental stages of the technologies. Eligible technologies included UK- or EU-licensed medicines repurposed as antiviral therapies for the viruses of interest. Vaccines, unlicensed medicines, and already approved treatments for the targeted viruses were excluded. Results A total of 196 repurposed technologies targeting the viruses were identified from published literature, and the expanded search on the clinical trials registry yielded 58 technologies in active clinical development. Interventional clinical trial activity was limited to influenza and COVID-19, with 29 technologies for COVID-19 and two for influenza advancing to phase III evaluation. For other viruses, proposed antiviral candidates were identified in the literature but had not progressed into clinical development. Commonly investigated pharmacological classes included direct-acting antivirals, tyrosine kinase inhibitors, immunomodulators, and anti-inflammatory agents. Conclusion Repurposing antiviral medicines represents a pragmatic strategy for rapid therapeutic deployment against emerging viral threats. Collaboration among researchers, policymakers, research funders, and regulatory bodies will be essential to improve pandemic preparedness and support repurposing efforts in emergency situations.

Background: The COVID-19 pandemic caused by SARS-CoV-2 is an unparalleled health risk, needing fast antiviral medication development. One of the most effective strategies for developing therapies against novel and emerging viruses is drug repurposing. Recently, systems biology approaches toward the discovery of repurposing medications are gaining prominence. Aim: This study aimed to implement a systems biology approach to identify crucial drug targets as well as potential drug candidates against COVID infection. Methods: Our approach utilizes differential gene expression in COVID conditions that enable the construction of a protein-protein interaction (PPI) network. Core clusters were extracted from this network, followed by molecular enrichment analysis. This process identified critical drug targets and potential drug candidates targeting various stages of COVID-19 infection. Results: The network was built using the top 200 differently expressed genes in mild, moderate, and severe COVID-19 infections. Top 3 clusters for each disease condition were identified, representing the core mechanism of the network. Molecular enrichment revealed the majority of the pathways in the mild state were associated with transcription regulation, protein folding, angiogenesis, and cytokine-signaling pathways. Whereas, the enriched pathways in moderate and severe disease states were predominately linked with the immune system and apoptotic processes, which include NF-kappaB signaling, cytokine signaling, TNF-mediated signaling, and oxidative stress-induced cell death. Further analysis identifies 28 potential drugs that can be repurposed to treat moderate and severe COVID-19, most of which are currently used in cancer treatment. Conclusion: Interestingly, some of the proposed drugs have demonstrated inhibitory effects against SARS-CoV-2, as supported by literature evidence. Overall, the drug repurposing method described here will help develop potential antiviral medications to treat emerging COVID strains.

Abstract The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Through CRISPR screening, we identified host genes required for infection by each variant. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed Food and Drug Administration-approved drugs. All the drugs were highly active against all the variants tested, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early virus replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanised mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.

The total cases of novel corona virus (SARS-CoV-2) infections is more than one million and total deaths recorded is more than fifty thousand. The research for developing vaccines and drugs against SARS-CoV-2 is going on in different parts of the world. Aim of the present study was to identify potential drug candidates against SARS-CoV-2 from existing drugs using in silico molecular modeling and docking. The targets for the present study was the spike protein and the main protease of SARS-CoV-2. The study was able to identify some drugs that can either bind to the spike protein receptor binding domain or the main protease of SARS-CoV-2. These include some of the antiviral drugs. These drugs might have the potential to inhibit the infection and viral replication.