Increasing membrane permeability of carboxylic acid-containing drugs using synthetic transmembrane anion transporters

Salam, Rayhanus; Chowdhury, Surid Mohammad; Marshall, Sarah R; Gneid, Hassan; Busschaert, Nathalie

doi:10.1039/d1cc02327f

Cited by 5 publications

(14 citation statements)

References 20 publications

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“…Lung sections were microscopically examined for pathology and evaluated for different pathological scores considering in ammation (alveolar and bronchial), haemorrhage and consolidation. The scores and parameters were graded as absent (0), minimal/mild (1), moderate (2), or severe (3). Lung pathology in the DMSO-treated mice included alveolar damage with interstitial lesions, in ammation, accumulation of immune effector cells, bronchial lining lesion, evidence of cell death and haemorrhage.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds with similar chemical properties as DPUDs were previously reported to transport anions, including Cl -, across lipid membranes. 3,17 Since Clplays a critical role in membrane-tra cking and provides the main electrical shunt for endocytic organelle acidi cation, 4 we hypothesized that the observed impairment of endocytosis by DPUDs could be linked to dysregulated Cltransport. We, therefore, examined the effect of DPU and DPUD treatment on Cltransport across membranes using an in vitro assay with large unilamellar vesicles (LUVs) containing a Cl --sensitive uorophore, lucigenin.…”

Section: Resultsmentioning

confidence: 99%

“…1,3-diphenyl urea (DPU) did not exhibit any inhibitory effect against the viruses. Compounds similar to DPUDs were reported to transport chloride (Cl -) across lipid membrane, 3 and changes in subcellular Clconcentration and transport were found to affect vesicular tra cking and endosomal acidi cation. 4 Using large unilamellar vesicle (LUV)-based in vitro Cltransport assay and by expressing a genetically-encoded YFP Clsensor in cells, we con rmed that DPUDs transported Clacross lipid membrane and led to intracellular Claccumulation, which possibly impacted intracellular virus tra cking.…”

Section: Introductionmentioning

confidence: 99%

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Diphenylurea derivatives broadly inhibit SARS-CoV-2 and influenza A virus infections by perturbing endocytic trafficking

Kumar

Taily

Singh

et al. 2022

Preprint

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Rapid evolution of SARS-CoV-2 and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals, 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. Through high-content screening, we have identified diphenylurea derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains in tissue culture cells, without affecting cell viability. We found, DPUDs transported chloride ions into the cell, and interfered with the endocytic machinery by perturbing intracellular chloride homeostasis. Finally, we tested DPUDs in mice challenged with SARS-CoV-2 and IAV. Treatment with DPUDs led to remarkable body weight recovery, improved survival, and significant reduction in lung viral load, indicating their potential as broad-acting antivirals.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diphenylurea derivatives broadly inhibit SARS-CoV-2 and influenza A virus infections by perturbing endocytic trafficking

Kumar

Taily

Singh

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…(3) A third set of case studies derived factors for optimizing drug solubility and permeability: (i) the role of polymers, (ii) fluorine hydrophobic/lipophilic effect, (iii) low lipophilicity amines (C2/C3 per N; e.g., i -Pr-NH 2 , piperazine) ,, and carboxylic acids (C2/C3 per COOH group; malic, glutaric acid) ,, as coformers, (iv) coamorphization of the drug in a fixed stoichiometry as nanoparticles , with additives, and (v) diphenyl urea as transmembrane anion transporter …”

Section: Models For Diffusion/permeability Enhancement In Pharmaceuti...mentioning

confidence: 99%

Diffusion and Flux Improvement of Drugs through Complexation

2023

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Improving the solubility and permeability of drugs via cocrystallization is an important theme in crystal engineering with practical applications for the discovery and development of high bioavailability medicines. The past decade has witnessed a surge of publications on pharmaceutical cocrystals/salts to improve the permeability of Biopharmaceutics Classification System (BCS) class IV drugs. In this review article, the reader is introduced to the fundamentals of drug permeability mechanisms and then examples of pharmaceutical cocrystals and salts designed to enhance drug diffusion and permeability are presented, in order to understand the different structural factors that modulate drug flux and transport across a semipermeable membrane. Broadly, two main phenomena can be summarized from the 50 or so examples: (1) The heterosynthons in hydrogen-bonded drug–coformer aggregates survive long enough in the experimental media such that the drug, which is present in high concentration due to supersaturation, exhibits higher flux across the semipermeable membrane. (2) The coformer or cocrystal is able to reduce the transepithelial electrical resistance (TEER) values of lipid monolayers, which impairs their tight junctions, and facilitates drug passage to improve its diffusion/permeability. The medicinal chemistry literature on high permeability drugs is recapitulated with the idea that these principles may be utilized in the de novo design of high permeability coformers for the synthesis of improved-performance pharmaceutical cocrystals. Enhancing drug solubility and permeability without changing its molecular structure in supramolecular complexes of pharmaceutical cocrystals and salts will address the poor bioavailability challenge for a majority of BCS class II and IV drugs.

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“…4g,h). Previous studies demonstrated, some synthetically-modi ed DPU analogues, but not DPU, are capable of transporting anions, including chloride ions, across lipid membranes 22,23 . Since chloride ions play a critical role in membrane-tra cking and provide the main electrical shunt for endocytic organelle acidi cation 24 , we hypothesized that the observed endocytic impairments by DPUDs could be linked to dysregulated chloride transport by the compounds.…”

mentioning

confidence: 99%

1,3-Diphenylurea derivatives inhibit cellular entry of influenza A virus and SARS-CoV-2

Kumar

Taily

Singh

et al. 2022

Preprint

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Influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly contagious pathogens that cause severe respiratory illnesses, often leading to hospitalization and death. Rapid emergence of mutant viral strains and waning immunity in the vaccinated individuals represent major challenges in the global fight against both the viruses. Complementing vaccine protection, a search for new therapeutic agents, effective against the existing and emerging viral strains, is an urgent priority. In this study, we identified 1,3-diphenylurea derivatives (DPUDs) as a new class of potential antiviral agents that robustly inhibited infections by different strains of IAV and SARS-CoV-2. Our study revealed, DPUDs primarily target the host cell entry of the viruses. That DPUDs affect the host processes exploited by IAV and SARS-CoV-2 for cellular entry, they are expected to be broadly effective against other related viruses that co-opt the same entry pathways.

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Increasing membrane permeability of carboxylic acid-containing drugs using synthetic transmembrane anion transporters

Abstract: Simple 1,3-diphenylureas are capable of transporting carboxylic acid-based drugs across phospholipid bilayers without affecting the permeability of other physiological anions such as chloride.

Cited by 5 publications

References 20 publications

Diphenylurea derivatives broadly inhibit SARS-CoV-2 and influenza A virus infections by perturbing endocytic trafficking

Diphenylurea derivatives broadly inhibit SARS-CoV-2 and influenza A virus infections by perturbing endocytic trafficking

Diffusion and Flux Improvement of Drugs through Complexation

1,3-Diphenylurea derivatives inhibit cellular entry of influenza A virus and SARS-CoV-2

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