The Next Generation COVID-19 Antiviral; Niclosamide-Based Inorganic Nanohybrid System Kills SARS-CoV-2
Goeun Choi1,2,3, N Sanoj Rejinold1, Huiyan Piao1
1Intelligent Nanohybrid Materials Laboratory (INML), Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.
Abstract:
The coronavirus disease 2019 (COVID-19) pandemic is a serious global threat with surging new variants of concern. Although global vaccinations have slowed the pandemic, their longevity is still unknown. Therefore, new orally administrable antiviral agents are highly demanded. Among various repurposed drugs, niclosamide (NIC) is the most potential one for various viral diseases such as COVID-19, SARS (severe acute respiratory syndrome), MERS (middle east respiratory syndrome), influenza, RSV (respiratory syncytial virus), etc. Since NIC cannot be effectively absorbed, a required plasma concentration for antiviral potency is hard to maintain, thereby restricting its entry into the infected cells. Such a 60-year-old bioavailability challenging issue has been overcome by engineering with MgO and hydroxypropyl methylcellulose (HPMC), forming hydrophilic NIC-MgO-HPMC, with improved intestinal permeability without altering NIC metabolism as confirmed by parallel artificial membrane permeability assay. The inhibitory effect on SARS-CoV-2 replication is confirmed in the Syrian hamster model to reduce lung injury. Clinical studies reveal that the bioavailability of NIC hybrid drug can go 4 times higher than the intact NIC. The phase II clinical trial shows a dose-dependent bioavailability of NIC from hybrid drug suggesting its potential applicability as a game changer in achieving the much-anticipated endemic phase.
Insights
A new hydrophilic formulation of niclosamide (NIC) enhances its absorption, improving oral antiviral efficacy against viruses like SARS-CoV-2. This breakthrough addresses bioavailability challenges, offering a potential game-changer for managing viral diseases.
Area of Science:
- Pharmaceutical Sciences
- Virology
- Drug Delivery
Background:
- The COVID-19 pandemic necessitates new orally administered antiviral drugs due to evolving variants and unknown vaccine longevity.
- Niclosamide (NIC) shows broad-spectrum antiviral potential against SARS-CoV-2, SARS, MERS, influenza, and RSV.
- Poor oral bioavailability and low plasma concentration limit NIC's therapeutic effectiveness, hindering its entry into infected cells.
Purpose of the Study:
- To overcome the bioavailability challenges of niclosamide (NIC).
- To develop an orally administrable antiviral agent with improved efficacy for viral diseases, including COVID-19.
- To enhance intestinal permeability and maintain therapeutic plasma concentrations of NIC.
Main Methods:
- Engineered NIC with MgO and hydroxypropyl methylcellulose (HPMC) to create a hydrophilic NIC-MgO-HPMC formulation.
- Assessed intestinal permeability using parallel artificial membrane permeability assay (PAMPA).
- Evaluated SARS-CoV-2 replication inhibition and lung injury reduction in a Syrian hamster model.
- Conducted clinical studies to determine the bioavailability of the NIC hybrid drug.
Main Results:
- The NIC-MgO-HPMC formulation significantly improved intestinal permeability without altering NIC metabolism.
- The hybrid drug demonstrated inhibitory effects on SARS-CoV-2 replication and reduced lung injury in animal models.
- Clinical trials showed up to a 4-fold increase in bioavailability for the NIC hybrid drug compared to intact NIC.
- Phase II clinical trials indicated dose-dependent bioavailability of NIC from the hybrid formulation.
Conclusions:
- Engineered hydrophilic NIC-MgO-HPMC formulation effectively overcomes the long-standing bioavailability issues of niclosamide.
- The enhanced NIC formulation exhibits significant antiviral potential and improved pharmacokinetic properties, suggesting its promise as an oral therapeutic.
- This development represents a potential game-changer for managing viral infections and transitioning towards an endemic phase.
