Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Jin, Geun‐woo; Choi, Gun; Piao, Huiyan; Ryu, Young Bae; Kwon, Hyung Jun; Lee, In Chul

doi:10.1101/2022.07.19.500639

Cited by 2 publications

(1 citation statement)

References 57 publications

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“…However, the in vivo use of niclosamide against SARS-CoV-2 infection was limited due to its low aqueous solubility and poor bioavailability [ 60 ]. An oral formulation of niclosamide with magnesium oxide and hydroxy propyl methyl cellulose (NIC-MgO-HPMC) was tested in Syrian hamster model of SARS-CoV-2 infection, which showed potent activity against the virus [ 61 ]. Recently, a screen of peptidomimetic tetrapeptide compounds identified N-0385, which afforded high level of therapeutic and prophylactic benefit against SARS-CoV-2 in hACE2-expressing mice.…”

Section: Discussionmentioning

confidence: 99%

Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo

et al. 2023

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Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl-) across lipid membrane and since intracellular Cl- concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl- gradient across the cell membrane. Using in vitro assays we demonstrated that the DPUDs transported Cl- into the cell and led to intracellular Cl- accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl- homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.

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Section: Discussionmentioning

confidence: 99%

Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo

et al. 2023

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The Next Generation COVID‐19 Antiviral; Niclosamide‐Based Inorganic Nanohybrid System Kills SARS‐CoV‐2

Choi,

Rejinold,

Piao

et al. 2023

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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.

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Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Cited by 2 publications

References 57 publications

Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo

Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo

The Next Generation COVID‐19 Antiviral; Niclosamide‐Based Inorganic Nanohybrid System Kills SARS‐CoV‐2

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