Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection
et al., International Journal of Nanomedicine, doi:10.2147/IJN.S448005, Mar 2024
22nd treatment shown to reduce risk in
April 2021, now with p = 0.00063 from 29 studies.
No treatment is 100% effective. Protocols
combine treatments.
6,200+ studies for
200+ treatments. c19early.org
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In vitro study showing that lactoferrin, camostat mesylate, and carrageenan inhibit SARS-CoV-2 pseudovirus infection in airway epithelial Calu-3 cells. All show dose-dependent inhibition. The study focuses on novel LNP formulations and the combination of carrageenan with the authors' LNP-PEP formulation containing ACE2 peptide showed significantly higher inhibition compared to carrageenan alone.
13 preclinical studies support the efficacy of TMPRSS2 inhibitors for COVID-19:
Study covers iota-carrageenan, lactoferrin, and TMPRSS2 inhibitors.
1.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
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González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.
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Umar et al., Inhibitory potentials of ivermectin, nafamostat, and camostat on spike protein and some nonstructural proteins of SARS-CoV-2: Virtual screening approach, Jurnal Teknologi Laboratorium, doi:10.29238/teknolabjournal.v11i1.344.
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Unal et al., Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2, bioRxiv, doi:10.1101/2022.01.11.475889.
5.
Sgrignani et al., Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2, Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626.
6.
Yathindranath et al., Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection, International Journal of Nanomedicine, doi:10.2147/IJN.S448005.
7.
Martins et al., In Vitro Inhibition of SARS-CoV-2 Infection by Bromhexine hydrochloride, bioRxiv, doi:10.1101/2022.12.23.521817.
8.
Schultz et al., Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2, Nature, doi:10.1038/s41586-022-04482-x.
9.
Hempel et al., Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties, Chemical Science, doi:10.1039/D1SC01494C.
Yathindranath et al., 28 Mar 2024, peer-reviewed, 5 authors.
Contact: donald.miller@umanitoba.ca.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection
International Journal of Nanomedicine, doi:10.2147/ijn.s448005
Purpose: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lingering threat to public health has fueled the search for effective therapeutics to treat SARS-CoV-2. This study aimed to develop lipid nanoparticle (LNP) inhibitors of SARS-CoV-2 entry to reduce viral infection in the nose and upper airway. Methods: Two types of LNP formulations were prepared following a microfluidic mixing method. The LNP-Trap consisted of DOPC, DSPC, cholesterol, and DSPE-PEG-COOH modified with various spike protein binding ligands, including ACE2 peptide, recombinant human ACE2 (rhACE2) or monoclonal antibody to spike protein (mAb). The LNP-Trim consisted of ionizing cationic DLin-MC3-DMA, DSPC, cholesterol, and DMG-PEG lipids encapsulating siACE2 or siTMPRSS2. Both formulations were assayed for biocompatibility and cell uptake in airway epithelial cells (Calu-3). Functional assessment of activity was performed using SARS-CoV-2 spike protein binding assays (LNP-Trap), host receptor knockdown (LNP-Trim), and SARS-CoV-2 pseudovirus neutralization assay (LNP-Trap and LNP-Trim). Localization and tissue distribution of fluorescently labeled LNP formulations were assessed in mice following intranasal administration. Results: Both LNP formulations were biocompatible based on cell impedance and MTT cytotoxicity studies in Calu-3 cells at concentrations as high as 1 mg/mL. LNP-Trap formulations were able to bind spike protein and inhibit pseudovirus infection by 90% in Calu-3 cells. LNP-Trim formulations reduced ACE2 and TMPRSS2 at the mRNA (70% reduction) and protein level (50% reduction). The suppression of host targets in Calu-3 cells treated with LNP-Trim resulted in over 90% inhibition of pseudovirus infection. In vivo studies demonstrated substantial retention of LNP-Trap and LNP-Trim in the nasal cavity following nasal administration with minimal systemic exposure. Conclusion: Both LNP-Trap and LNP-Trim formulations were able to safely and effectively inhibit SARS-CoV-2 pseudoviral infection in airway epithelial cells. These studies provide proof-of-principle for a localized treatment approach for SARS-CoV-2 in the upper airway.
Disclosure
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