Polyoxometalates Can Be Repurposed As Broad-Spectrum Antivirals Against Various Human Respiratory Viruses

Medical News: Respiratory viruses pose a significant threat to public health, causing widespread infections and imposing substantial burdens on healthcare systems and economies globally. Despite the prevalence and impact of these viruses, specific antiviral treatments targeting them remain elusive. The emergence of drug-resistant viral strains further complicates the situation, emphasizing the urgent need for novel antiviral agents. In this context, recent research conducted by scientists at the University of Turin in Italy and Constructor University in Germany that is covered in this Medical News report, has shed light on the potential of polyoxometalates (POMs) as broad-spectrum antivirals against various human respiratory viruses.


Polyoxometalates As Broad-Spectrum Antivirals Against Various Human Respiratory Viruses
Investigation of the antiviral mechanism of action of Ti2PW10. (A, C) Time-of-addition assays. Cells were treated with serial dilutions of Ti2PW10 (100 to 0.4 μM) before infection (pre), during virus entry (entry) or after treatment with NH4Cl (post-entry). Viral infectivity was assessed 24 h (HRV-A1) (A) or 16 h (HCoV-OC43) (B) after infection. The percent infection (%) was calculated by comparing treated and untreated wells. Error bars represent SEMs for three independent experiments. (B, D) Binding assays. The effect of Ti2PW10 on the binding of HRV-A1 (B) or HCoV-OC43 (D) to host cells was assessed via binding assays. On y-axis, virus titers are expressed as focus forming units per mL (FFU/mL). Student’s t-test was used to compare viral titers (n.s.: not significant; **: p-value <0.01). UT, untreated. (E) Ti2PW10 cell uptake. Uninfected HeLa or MRC-5 cells were treated with fluorescent Ti2PW10 for 5 min, 1 h, and 3 h. POM cell distribution in live cells was observed in red via confocal laser microscopy. Control sample (untreated) was incubated with culture medium alone. Magnification, 400×.
 
Polyoxometalates: An Overview of a Promising Antiviral Class
Polyoxometalates represent a class of inorganic compounds with unique structural and compositional properties. Their negative charge and diverse molecular characteristics make them attractive candidates for biomedical applications, including antiviral therapy. Previous studies have highlighted the broad biological activities of POMs, ranging from anti-tumor effects to antimicrobial and antiviral properties. Notably, their ability to modulate their properties at the molecular level offers versatility in targeting different pathogens.
 
Identifying Potent Antivirals: Ti2PW10 Emerges as a Promising Candidate
In the study conducted by researchers, two specific POMs, namely [TiW11CoO40]8- (TiW11Co) and [Ti2PW10O40]7- (Ti2PW10), were evaluated for their antiviral potential against a range of human respiratory viruses. Among these, Ti2PW10 demonstrated remarkable broad-spectrum activity against enveloped and non-enveloped viruses, including coronavirus (HCoV-OC43), rhinovirus (HRV-A1), respiratory syncytial virus (RSV-A2), and adenovirus (AdV-5). Importantly, Ti2PW10 exhibited high selectivity indexes (SIs >700), indicating its potency and specificity in inhibiting viral replication.
 
Unraveling the Mechanism of Action: Ti2PW10 as an Entry Inhibitor
Further investigations into Ti2PW10's mode of action revealed its role as an entry inhibitor for respiratory viruses. Unlike some antivirals that target viral replication or protein synthesis, Ti2PW10 specifically interferes with the virus's ability to enter host cells. This mechanism was validated across different cell types and viral strains, highlighting Ti2PW10's broad applicability against diverse respiratory viruses.
 
Challenges and Solutions: Addressing Antiviral Resistance and Delivery
One of the major challenges in antiviral therapy is the development of drug-resistant viral strains. However, Ti2PW10 demonstrated a high barrier to the emergence of resistant variants, making it a promising candidate for long-term therapeutic use. Additionally, the study proposed a novel mucoadhesive thermosensitive in situ hydrogel formulation for nasal delivery of Ti2PW10. This formulation not only enhances the drug's concentration at the infection site but also minimizes systemic exposure, thereby improving efficacy and reducing potential side effects.
 
Validating Efficacy: In Vitro and In Vivo Models
To assess Ti2PW10's therapeutic potential, researchers utilized advanced in vitro models, including a 3D human nasal epithelial tissue culture. The results demonstrated Ti2PW10's ability to accelerate viral clearance without causing cytotoxicity or tissue damage, underscoring its safety and efficacy in relevant physiological contexts.
 
Overall Study Findings And Key Points
Ti2PW10 was found to inhibit replication of multiple HCoV and HRV strains, in different cell systems. Ti2PW10 did not affect virus binding or intracellular viral replication, but selectively inhibited the viral entry. Serial passaging of virus in presence of the POM revealed a high barrier to development of Ti2PW10-resistant variants of HRV-A1 or HCoV-OC43. Moreover, Ti2PW10 was able to inhibit HRV-A1 production in a 3D model of the human nasal epithelium and, importantly, the antiviral treatment did not determine cytotoxicity or tissue damage. A mucoadhesive thermosensitive in situ hydrogel formulation for nasal delivery was also developed for Ti2PW10. Overall, good biocompatibility on cell lines and human nasal epithelia, broad-spectrum activity, and absence of antiviral resistance development reveal the potential of Ti2PW10 as an antiviral candidate for the development of a treatment of acute respiratory viral diseases, warranting further studies to identify the specific target/s of the polyanion and assess its clinical potential.
 
Polyoxometalate Ti2PW10 exerts broad-spectrum inhibition against human respiratory viruses, with good biocompatibility.
 
Key Takeaways:
 
-Ti2PW10 acts by hampering virus entry into host cells.
 
-Ti2PW10 does not rapidly select drug-resistant virus strains.
 
-The study confirmed Ti2PW10 anti-HRV activity on an in vitro 3D model of the human upper respiratory tract.
 
-A novel mucoadhesive thermosensitive in situ hydrogel formulation is proposed for the nasal delivery of Ti2PW10.
 
Future Directions and Implications
The findings from this study pave the way for further exploration of Ti2PW10 as a viable antiviral candidate against respiratory infections. Future research efforts may focus on elucidating the specific molecular targets of Ti2PW10 within the viral entry process, as well as conducting comprehensive toxicological studies to ensure its safety for clinical applications. Moreover, the development of optimized drug delivery systems, such as the mucoadhesive hydrogel formulation proposed, holds promise for enhancing Ti2PW10's therapeutic outcomes in clinical settings.
 
Conclusion: Ti2PW10 - A Promising Broadspectrum Antiviral Agent
In conclusion, the discovery of Ti2PW10 as a potent and broad-spectrum antiviral represents a significant advancement in the field of respiratory virus treatment. Its ability to inhibit viral entry, coupled with its favorable safety profile and resistance barrier, positions Ti2PW10 as a promising candidate for further development into a clinically effective antiviral therapy. As researchers continue to unravel its mechanisms and optimize delivery strategies, Ti2PW10 may emerge as a frontline defense against respiratory viral infections, offering hope for improved patient outcomes and public health resilience.
 
The study findings were published in the peer reviewed journal Antiviral Research.
https://www.sciencedirect.com/science/article/pii/S0166354224001062
 
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