GS-441524 for COVID-19

Preclinical pharmacokinetics (PK) and In Vitro ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in vitro in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62–78% across all studied species. The in vitro transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CLp), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vdss) ranged from 0.9 L/kg in dogs to 2.4 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.

The COVID‐19 pandemic has underscored the urgent need for broad‐spectrum antivirals (BSAs) capable of countering diverse and rapidly emerging viral threats. Unlike virus‐specific drugs, BSAs offer cross‐family protection and can serve as adaptable therapeutic platforms for pandemic preparedness. Advances in nanotechnology have further strengthened this approach by improving the solubility, stability, and targeted delivery of antiviral agents. Several repurposed drugs, such as niclosamide, favipiravir, remdesivir, nitazoxanide, and zinc‐ionophores, have demonstrated potential broad‐spectrum activity when formulated at the nanoscale. These nanoengineered platforms enhance pharmacokinetic performance, tissue penetration, and bioavailability, thereby enabling lower effective doses and reduced systemic toxicity. Such nanotechnological strategies not only improve antiviral efficacy across multiple viral families, including Coronaviridae, Flaviviridae, Orthomyxoviridae, and Poxviridae, but also support scalable, cost‐effective production suitable for global deployment. By integrating drug repurposing with nanoengineering, BSAs can form the cornerstone of future pandemic preparedness, bridging the gap between laboratory innovation and rapid clinical response to emerging infectious diseases.

ABSTRACT The emergence of SARS‐CoV‐2 posed a major global public health threat, necessitating urgent development of therapeutics. Despite vaccine availability, continuous emergence of viral variants with enhanced transmissibility and immune escape capabilities, and consequential impacts on health services, requires effective antiviral therapeutics. Drug repurposing offers an expeditious strategy to identify therapeutics with established safety profiles. We implemented a comprehensive three‐tiered validation approach, screening 2,570 compounds against SARS‐CoV‐2 in vitro, followed by ex vivo validation in well‐differentiated primary human bronchial epithelial cell (WD‐PBEC) cultures, and rigorous in vivo assessment. This methodical progression identified Azatadine‐Dimaleate, a H1‐receptor antagonist, as an exceptional candidate with consistent efficacy across all systems. Azatadine‐Dimaleate demonstrated potent antiviral activity‐ EC50: 4.0 µM (95% CI: 3.2–4.8 µM), reducing viral replication by ~5,000‐fold at 25 µM in epithelial cultures and lowering peak viral titers in WD‐PBECs by 1.4 log 10 , and 2.33 log 10 at 48 and 96 hpi, respectively, compared to controls. There was also a concomitant reduction in expression of interferons and pro‐inflammatory genes, including IL‐6. Combination with Remdesivir synergistically enhanced antiviral activity, reducing the EC50 of both drugs by > 60%. In the K18‐hACE2 transgenic mouse model, Azatadine‐Dimaleate significantly reduced weight loss (4% vs. 12%, p ≤ 0.05), decreased viral loads, and halved viral antigen expression in lung tissues. Unlike many candidates that faltered in complex models, Azatadine‐Dimaleate maintained efficacy across all platforms. These findings support its clinical evaluation, alone or in combination with Remdesivir, as a versatile therapeutic with strong potential to address current and emerging SARS‐CoV‐2 variants.

Since the onset of the COVID-19 pandemic, remarkable progress has been made in the development of antiviral therapies for SARS-CoV-2. Several direct-acting antivirals, such as remdesivir, molnupiravir, and nirmatrelvir/ritonavir, offer clinical benefits. These agents have significantly contributed to reducing the viral loads and duration of the illness, as well as the disease’s severity and mortality. However, despite these advances, important limitations remain. The continued emergence of resistant SARS-CoV-2 variants highlights the urgent need for adaptable and durable therapeutic strategies. Therefore, this review aims to provide an updated overview of the main antiviral strategies that are used and the discovery of new drugs against SARS-CoV-2, as well as the therapeutic limitations that have shaped clinical management in recent years. The major challenges include resistance associated with viral mutations, limited treatment windows, and unequal access to treatment. Moreover, there is an ongoing need to identify novel compounds with broad-spectrum activity, improved pharmacokinetics, and suitable safety profiles. Combination treatment regimens represent a promising strategy to increase the efficacy of treating COVID-19 while minimizing the potential for resistance. Ideally, these interventions should be safe, affordable, and easy to administer, which would ensure broad global access and equitable treatment and enable control of COVID-19 cases and preparedness for future threats.

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease spreads quickly due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties, as well as computer-aided drug design (in-silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

AbstractTo identify potential therapeutic stop-gaps for SARS-CoV-2, we evaluated a library of 1,670 approved and reference compounds in an unbiased, cellular image-based screen for their ability to suppress the broad impacts of the SARS-CoV-2 virus on phenomic profiles of human renal cortical epithelial cells using deep learning. In our assay, remdesivir is the only antiviral tested with strong efficacy, neither chloroquine nor hydroxychloroquine have any beneficial effect in this human cell model, and a small number of compounds not currently being pursued clinically for SARS-CoV-2 have efficacy. We observed weak but beneficial class effects of β-blockers, mTOR/PI3K inhibitors and Vitamin D analogues and a mild amplification of the viral phenotype with β-agonists.

The novel coronavirus disease (COVID-19) continues to endanger human health, and its therapeutic drugs are under intensive research and development. Identifying the efficacy and toxicity of drugs in animal models is helpful for further screening of effective medications, which is also a prerequisite for drugs to enter clinical trials. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invades host cells mainly by the S protein on its surface. After the SARS-CoV-2 RNA genome is injected into the cells, M protein will help assemble and release new viruses. RdRp is crucial for virus replication, assembly, and release of new virus particles. This review analyzes and discusses 26 anti-SARS-CoV-2 drugs based on their mechanism of action, effectiveness and safety in different animal models. We propose five drugs to be the most promising to enter the next stage of clinical trial research, thus providing a reference for future drug development.