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Back to the Basics of SARS-CoV-2 Biochemistry: Microvascular Occlusive Glycan Bindings Govern Its Morbidities and Inform Therapeutic Responses

Scheim et al., Viruses, doi:10.3390/v16040647, NCT04727424
Apr 2024  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 110 treatments. c19ivm.org
Review of the biochemical underpinnings of the severe morbidities of COVID-19, focusing on the binding of the SARS-CoV-2 spike protein (SP) to sialylated glycans on host cell surfaces. Authors highlight how the SP attaches particularly tightly to the trillions of red blood cells (RBCs), platelets, and endothelial cells in the human body, triggering blood cell aggregation, microvascular occlusion, and vascular damage that lead to the hypoxia, blood clotting, and related morbidities of severe COVID-19. Authors note that RBC aggregation experimentally induced in several animal species caused most of the same morbidities of severe COVID-19, and suggest that the glycan biochemistry is important for understanding the efficacy of certain generic COVID-19 treatments like ivermectin.
The authors suggest that ivermectin may be an effective treatment for COVID-19 due to its ability to competitively bind to the SARS-CoV-2 spike protein and prevent the protein's attachment to host cell glycans. In silico studies found that ivermectin binds with high affinity to multiple sites on the spike protein, especially on the N-terminal domain, which governs the protein's glycan interactions. Clinical studies observed rapid normalization of peripheral oxygen saturation in severe COVID-19 patients treated with ivermectin, which parallels the rapid disaggregation of ivermectin-treated red blood cell clumps in vitro. Authors note that these benefits may be less relevant for milder infections with reduced penetration into the bloodstream.
The authors suggest that treatments targeting the glycan-mediated pathology of COVID-19, particularly those that reduce red blood cell and platelet aggregation, may be beneficial for severe cases. Authors also discuss the potential of hydroxychloroquine and fluvoxamine in this context, as these treatments have been shown to reduce blood cell aggregation.
Reviews covering ivermectin for COVID-19 include1-45.
Review covers ivermectin, HCQ, and fluvoxamine.
Scheim et al., 22 Apr 2024, Australia, peer-reviewed, 8 authors, study period 7 July, 2021 - 1 April, 2023, trial NCT04727424 (history). Contact: dscheim@alum.mit.edu (corresponding author), p.parry1@uq.edu.au, aldousc@ukzn.ac.za.
This PaperIvermectinAll
Back to the Basics of SARS-CoV-2 Biochemistry: Microvascular Occlusive Glycan Bindings Govern Its Morbidities and Inform Therapeutic Responses
David E Scheim, Peter I Parry, David J Rabbolini, Colleen Aldous, Morimasa Yagisawa, Robert Clancy, Thomas J Borody, Wendy E Hoy
doi:10.3390/v16040000
Consistent with the biochemistry of coronaviruses as well established over decades, SARS-CoV-2 makes its initial attachment to host cells through the binding of its spike protein (SP) to sialylated glycans (containing the monosaccharide sialic acid) on the cell surface. The virus can then slide over and enter via ACE2. SARS-CoV-2 SP attaches particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial cells in the human body, each cell very densely coated with sialic acid surface molecules but having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses that express a sialic acid-cleaving enzyme are benign, while the other three-SARS, SARS-CoV-2 and MERS-are virulent. RBC aggregation experimentally induced in several animal species using an injected polysaccharide caused most of the same morbidities of severe COVID-19. This glycan biochemistry is key to disentangling controversies that have arisen over the efficacy of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. More broadly, disregard for the active physiological role of RBCs yields unreliable or erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold higher. Appreciation of the active role of RBCs can elucidate the microvascular underpinnings of other health conditions, including cardiovascular disease, and therapeutic opportunities to address them.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/v16040000/s1, Table S1 : Changes in SpO2 for 34 COVID-19 patients treated with IVM, doxycycline and zinc, as reported by Stone et al. (2022) , Table S2 : Changes in SpO2 for 19 COVID-19 patients treated with IVM, doxycycline and zinc, as reported by Hazan et al. (2021) , Table S3 : Changes in SpO2 for 19 COVID-19 patients treated with IVM, zinc and vitamin C, with some also given azithromycin and hydroxychloroquine, as reported by Babalola et al. (2021) , Table S4 : Changes in SpO2 for 26 COVID-19 patients treated without IVM using different combinations of lopinavir/ritonavir, remdesivir, azithromycin, enoxaparin, zinc sulfate and vitamin C, as reported by Thairu et al., Table S5 : Means and standard errors of SpO2 changes from day 0 to day 1 and from day 0 to day 2 for the full set of 26 patients from Thairu et al. (2022) and for the subset of 18 patients who were on room air (without oxygen supplementation or ventilation). Appendix A. Notes and Calculations on Surface Area and Extent of Sialylation of RBCs and Endothelial Cells in Human Vasculature In an average human adult, the blood contains 25 trillion RBCs [34, 35] , each with a surface area of 163 µm 2 [126], yielding a total surface area of about 4075 m 2 . The blood also contains nearly one trillion platelets [190] , and the vasculature is lined with one trillion endothelial cells having a total..
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SARS-CoV-2 SP attaches ' 'particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial ' 'cells in the human body, each cell very densely coated with sialic acid surface molecules but ' 'having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell ' 'aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood ' 'clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses ' 'that express a sialic acid-cleaving enzyme are benign, while the other three—SARS, SARS-CoV-2 ' 'and MERS—are virulent. RBC aggregation experimentally induced in several animal species using ' 'an injected polysaccharide caused most of the same morbidities of severe COVID-19. This ' 'glycan biochemistry is key to disentangling controversies that have arisen over the efficacy ' 'of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. ' 'More broadly, disregard for the active physiological role of RBCs yields unreliable or ' 'erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and ' 'other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold ' 'higher. 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