Computational Prediction of the Interaction of Ivermectin with Fibrinogen
et al., Molecular Sciences, doi:10.3390/ijms241411449, Jul 2023
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
In silico study showing that ivermectin may bind with high affinity to multiple sites on fibrinogen and may interfere with SARS-CoV-2 spike protein - fibrinogen binding, potentially inhibiting the formation of fibrin clots resistant to degradation (a hallmark of acute COVID-19 and long COVID).
74 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
1.
Gayozo et al., Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach, Biotecnia, doi:10.18633/biotecnia.v27.2485.
2.
Lefebvre et al., Characterization and Fluctuations of an Ivermectin Binding Site at the Lipid Raft Interface of the N-Terminal Domain (NTD) of the Spike Protein of SARS-CoV-2 Variants, Viruses, doi:10.3390/v16121836.
3.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
4.
Bagheri-Far et al., Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8, Molecular Biology Research Communications, doi:10.22099/mbrc.2024.50245.2001.
5.
de Oliveira Só et al., In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease, Preprints, doi:10.20944/preprints202404.1825.v1.
6.
Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.
7.
Oranu et al., Validation of the binding affinities and stabilities of ivermectin and moxidectin against SARS-CoV-2 receptors using molecular docking and molecular dynamics simulation, GSC Biological and Pharmaceutical Sciences, doi:10.30574/gscbps.2024.26.1.0030.
8.
Zhao et al., Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis, Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752.
9.
Vottero et al., Computational Prediction of the Interaction of Ivermectin with Fibrinogen, Molecular Sciences, doi:10.3390/ijms241411449.
10.
Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.
11.
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.
12.
Alvarado et al., Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT, Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692.
13.
Aminpour et al., In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, Computation, doi:10.3390/computation10040051.
14.
Parvez et al., Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host–pathogen interaction, pathogenicity, and possible drug therapeutics, Immunity, Inflammation and Disease, doi:10.1002/iid3.639.
15.
Francés-Monerris et al., Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection, Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C.
16.
González-Paz et al., Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach, Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677.
17.
González-Paz (B) et al., Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models, Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284.
18.
Rana et al., A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection, Research Square, doi:10.21203/rs.3.rs-755838/v1.
19.
Muthusamy et al., Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein, Journal of Virology & Antiviral Research, www.scitechnol.com/abstract/virtual-screening-reveals-potential-antiparasitic-drugs-inhibiting-the-receptor-binding-domain-of-sarscov2-spike-protein-16398.html.
20.
Qureshi et al., Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750.
21.
Schöning et al., Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains, Research Square, doi:10.21203/rs.3.rs-379291/v1.
22.
Bello et al., Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857.
23.
Udofia et al., In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV, Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2.
24.
Choudhury et al., Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach, Future Medicine, doi:10.2217/fvl-2020-0342.
25.
Kern et al., Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing, Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678.
26.
Saha et al., The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2, Structural Chemistry, doi:10.1007/s11224-021-01776-0.
27.
Eweas et al., Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2, Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908.
28.
Parvez (B) et al., Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach, International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098.
29.
Francés-Monerris (B) et al., Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent, ChemRxiv, doi:10.26434/chemrxiv.12782258.v1.
30.
Kalhor et al., Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2020.1824816.
31.
Swargiary, A., Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies, Research Square, doi:10.21203/rs.3.rs-73308/v1.
32.
Maurya, D., A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients, American Chemical Society (ACS), doi:10.26434/chemrxiv.12630539.v1.
33.
Lehrer et al., Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2, In Vivo, 34:5, 3023-3026, doi:10.21873/invivo.12134.
34.
Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.
35.
Kofler et al., M-Motif, a potential non-conventional NLS in YAP/TAZ and other cellular and viral proteins that inhibits classic protein import, iScience, doi:10.1016/j.isci.2025.112105.
36.
Shahin et al., The selective effect of Ivermectin on different human coronaviruses; in-vitro study, Research Square, doi:10.21203/rs.3.rs-4180797/v1.
37.
Jitobaom et al., Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin, Journal of Medical Virology, doi:10.1002/jmv.29552.
38.
Fauquet et al., Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction, Molecules, doi:10.3390/molecules28248072.
39.
García-Aguilar et al., In Vitro Analysis of SARS-CoV-2 Spike Protein and Ivermectin Interaction, International Journal of Molecular Sciences, doi:10.3390/ijms242216392.
40.
Liu et al., SARS-CoV-2 viral genes Nsp6, Nsp8, and M compromise cellular ATP levels to impair survival and function of human pluripotent stem cell-derived cardiomyocytes, Stem Cell Research & Therapy, doi:10.1186/s13287-023-03485-3.
41.
Boschi et al., SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects, bioRxiv, doi:10.1101/2022.11.24.517882.
42.
De Forni et al., Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients, PLoS ONE, doi:10.1371/journal.pone.0276751.
43.
Saha (B) et al., Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder, Pharmaceutics, doi:10.3390/pharmaceutics14071432.
44.
Jitobaom (B) et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.
45.
Croci et al., Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin, International Journal of Biomaterials, doi:10.1155/2016/8043983.
46.
Zheng et al., Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121719.
47.
Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.
48.
Liu (B) et al., Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes, Stem Cell Reports, doi:10.1016/j.stemcr.2022.01.014.
49.
Segatori et al., Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients, Viruses, doi:10.3390/v13102084.
50.
Jitobaom (C) et al., Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-941811/v1.
51.
Munson et al., Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line, British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021, web.archive.org/web/20230401070026/https://michealmunson.github.io/COVID.pdf.
52.
Mountain Valley MD, Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™, www.globenewswire.com/en/news-release/2021/05/18/2231755/0/en/Mountain-Valley-MD-Receives-Successful-Results-From-BSL-4-COVID-19-Clearance-Trial-on-Three-Variants-Tested-With-Ivectosol.html.
53.
Yesilbag et al., Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro, Virus Research, doi:10.1016/j.virusres.2021.198384.
54.
Mody et al., Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents, Communications Biology, doi:10.1038/s42003-020-01577-x.
55.
Jeffreys et al., Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2, International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2022.106542.
56.
Surnar et al., Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19, ACS Pharmacol. Transl. Sci., doi:10.1021/acsptsci.0c00179.
57.
Li et al., Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment, J. Cellular Physiology, doi:10.1002/jcp.30055.
58.
Caly et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research, doi:10.1016/j.antiviral.2020.104787.
59.
Zhang et al., Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflammation Research, doi:10.1007/s00011-008-8007-8.
60.
Gao et al., Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65, International Immunopharmacology, doi:10.1016/j.intimp.2024.112073.
61.
Abd-Elmawla et al., Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis, Journal of Zhejiang University-SCIENCE B, doi:10.1631/jzus.B2200385.
62.
Uematsu et al., Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model, The Journal of Antibiotics, doi:10.1038/s41429-023-00623-0.
63.
Albariqi et al., Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688.
64.
Errecalde et al., Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model, Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017.
65.
Madrid et al., Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation, Heliyon, doi:10.1016/j.heliyon.2020.e05820.
66.
Ma et al., Ivermectin contributes to attenuating the severity of acute lung injury in mice, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113706.
67.
de Melo et al., Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin, EMBO Mol. Med., doi:10.15252/emmm.202114122.
68.
Arévalo et al., Ivermectin reduces in vivo coronavirus infection in a mouse experimental model, Scientific Reports, doi:10.1038/s41598-021-86679-0.
69.
Chaccour et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Scientific Reports, doi:10.1038/s41598-020-74084-y.
70.
Yan et al., Anti-inflammatory effects of ivermectin in mouse model of allergic asthma, Inflammation Research, doi:10.1007/s00011-011-0307-8.
71.
Götz et al., Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Scientific Reports, doi:10.1038/srep23138.
72.
Tay et al., Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin, Antiviral Research, doi:10.1016/j.antiviral.2013.06.002.
73.
Wagstaff et al., Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochemical Journal, doi:10.1042/BJ20120150.
74.
Wagstaff (B) et al., An AlphaScreen®-Based Assay for High-Throughput Screening for Specific Inhibitors of Nuclear Import, SLAS Discovery, doi:10.1177/1087057110390360.
75.
Barrows et al., A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection, Cell Host & Microbe, doi:10.1016/j.chom.2016.07.004.
76.
Yang et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Research, doi:10.1016/j.antiviral.2020.104760.
77.
Mastrangelo et al., Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dks147.
78.
Varghese et al., Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses, Antiviral Research, doi:10.1016/j.antiviral.2015.12.012.
79.
Bennett et al., Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry, Virology, doi:10.1016/j.virol.2014.10.013.
80.
Kosyna et al., The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways, Biological Chemistry, doi:10.1515/hsz-2015-0171.
81.
Scheim et al., Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19, International Journal of Molecular Sciences, doi:10.3390/ijms242317039.
82.
Liu (C) et al., Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury, Frontiers in Immunology, doi:10.3389/fimmu.2023.1324021.
83.
Shouman et al., SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147, Cell Communication and Signaling, doi:10.1186/s12964-024-01718-3.
84.
Scheim (B), D., Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion, SSRN, doi:10.2139/ssrn.3636557.
85.
Scheim (C), D., From Cold to Killer: How SARS-CoV-2 Evolved without Hemagglutinin Esterase to Agglutinate and Then Clot Blood Cells, Center for Open Science, doi:10.31219/osf.io/sgdj2.
86.
Behl et al., CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target, Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072.
87.
DiNicolantonio et al., Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19, Open Heart, doi:10.1136/openhrt-2020-001350.
88.
Mothae et al., SARS-CoV-2 host-pathogen interactome: insights into more players during pathogenesis, Virology, doi:10.1016/j.virol.2025.110607.
89.
Hazan et al., Treatment with Ivermectin Increases the Population of Bifidobacterium in the Gut, ACG 2023, acg2023posters.eventscribe.net/posterspeakers.asp.
Vottero et al., 14 Jul 2023, peer-reviewed, 6 authors.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Computational Prediction of the Interaction of Ivermectin with Fibrinogen
International Journal of Molecular Sciences, doi:10.3390/ijms241411449
Hypercoagulability and formation of extensive and difficult-to-lyse microclots are a hallmark of both acute COVID-19 and long COVID. Fibrinogen, when converted to fibrin, is responsible for clot formation, but abnormal structural and mechanical clot properties can lead to pathologic thrombosis. Recent experimental evidence suggests that the spike protein (SP) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly bind to the blood coagulation factor fibrinogen and induce structurally abnormal blood clots with heightened proinflammatory activity. Accordingly, in this study, we used molecular docking and molecular dynamics simulations to explore the potential activity of the antiparasitic drug ivermectin (IVM) to prevent the binding of the SARS-CoV-2 SP to fibrinogen and reduce the occurrence of microclots. Our computational results indicate that IVM may bind with high affinity to multiple sites on the fibrinogen peptide, with binding more likely in the central, E region, and in the coiled-coil region, as opposed to the globular D region. Taken together, our in silico results suggest that IVM may interfere with SP-fibrinogen binding and, potentially, decrease the formation of fibrin clots resistant to degradation. Additional in vitro studies are warranted to validate whether IVM binding to fibrinogen is sufficiently stable to prevent interaction with the SP, and potentially reduce its thrombo-inflammatory effect in vivo.
Author Contributions: Conceptualization, A.D.S., D.E.S. and M.A.; methodology, M.A., P.V. and S.T.; software, P.V., S.T. and M.A.; validation, M.A., P.V., S.T. and A.D.S.; formal analysis, P.V., S.T. and M.A.; investigation, P.V., S.T., M.A. and A.D.S.; resources, J.A.T. and M.A.; data curation, P.V. and S.T.; writing-original draft preparation, P.V. and S.T.; writing-review and editing, D.E.S., A.D.S., M.A., P.V., S.T. and J.A.T.; visualization, P.V. and S.T.; supervision, M.A., A.D.S., D.E.S. and J.A.T.; project administration, M.A. and J.A.T. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: A.D.S. reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO, and grants and personal fees from EISAI. The other authors declare no conflict of interest.
Abbreviations The The highest scoring pose of the SP in both states is illustrated in green, the second pose in blue, and the third in orange. The binding pockets where IVM inhibits fibrinogen, which happen to be situated at the interface of SP and fibrinogen, are emphasized as follows: Site 3 and Site 12, both located in the central E region, are highlighted in yellow and dark green, respectively. Meanwhile, the gamma1 site stands out in cyan, and the gamma2 site in purple; Site 3b, as identified by the Site..
References
Aminpour, Cannariato, Preto, Safaeeardebili, Moracchiato et al., Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, doi:10.3390/computation10040051
Andrusier, Nussinov, Wolfson, Firedock, Fast Interaction Refinement in Molecular Docking, Proteins
Asakura, Ogawa, COVID-19-Associated Coagulopathy and Disseminated Intravascular Coagulation, Int. J. Hematol, doi:10.1007/s12185-020-03029-y
Barshtein, Wajnblum, Yedgar, Kinetics of Linear Rouleaux Formation Studied by Visual Monitoring of Red Cell Dynamic Organization, Biophys. J, doi:10.1016/S0006-3495(00)76791-9
Baskurt, Meiselman, Erythrocyte Aggregation: Basic Aspects and Clinical Importance, Clin. Hemorheol. Microcirc, doi:10.3233/CH-2012-1573
Becker, COVID-19 Update: COVID-19-Associated Coagulopathy, J. Thromb. Thrombolysis, doi:10.1007/s11239-020-02134-3
Berzuini, Bianco, Migliorini, Maggioni, Valenti et al., Red Blood Cell Morphology in Patients with COVID-19-Related Anaemia, Blood Transfus, doi:10.2450/2020.0242-20
Biondi, Gulati, Possick, Joseph, Singh et al., Unexplained dyspnea in a patient with a history of COVID-19, Chest, doi:10.1016/j.chest.2021.07.2054
Boschi, Scheim, Bancod, Militello, Bideau et al., SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects, Int. J. Mol. Sci, doi:10.3390/ijms232415480
Bullard, Chapter 41-CR3
Ceban, Ling, Lui, Lee, Gill et al., Fatigue and Cognitive Impairment in Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis, Brain Behav. Immun, doi:10.1016/j.bbi.2021.12.020
Couzin-Frankel, The Mystery of the Pandemic's 'Happy Hypoxia', Science, doi:10.1126/science.368.6490.455
Craddock, Mahajan, Spikes, Krishnamachary, Ram et al., Persistent Circulation of Soluble and Extracellular Vesicle-Linked Spike Protein in Individuals with Postacute Sequelae of COVID-19, J. Med. Virol, doi:10.1002/jmv.28568
Crump, Ivermectin: Enigmatic Multifaceted "wonder" Drug Continues to Surprise and Exceed Expectations, J. Antibiot, doi:10.1038/ja.2017.11
Darden, Duke, Giambasu, Gilson, Gohlke et al., None
Davalos, Akassoglou, Fibrinogen as a Key Regulator of Inflammation in Disease, Semin. Immunopathol, doi:10.1007/s00281-011-0290-8
Eberhardt, Santos-Martins, Tillack, Forli, AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings, J. Chem. Inf. Model, doi:10.1021/acs.jcim.1c00203
Edelsbrunner, Kirkpatrick, Seidel, On the Shape of a Set of Points in the Plane, IEEE Trans. Inf. Theory
Gattinoni, Coppola, Cressoni, Busana, Rossi et al., COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Am. J. Respir. Crit. Care Med, doi:10.1164/rccm.202003-0817LE
González-Durruthy, Rial, Cordeiro, Liu, Ruso, Exploring the Conformational Binding Mechanism of Fibrinogen Induced by Interactions with Penicillin β-Lactam Antibiotic Drugs, J. Mol. Liq, doi:10.1016/j.molliq.2020.114667
González-Durruthy, Scanavachi, Rial, Liu, Cordeiro et al., Mapping the Underlying Mechanisms of Fibrinogen Benzothiazole Drug Interactions Using Computational and Experimental Approaches, Int. J. Biol. Macromol, doi:10.1016/j.ijbiomac.2020.07.044
Grobbelaar, Venter, Vlok, Ngoepe, Laubscher et al., SARS-CoV-2 Spike Protein S1 Induces Fibrin(Ogen) Resistant to Fibrinolysis: Implications for Microclot Formation in COVID-19, Biosci. Rep, doi:10.1042/BSR20210611
Gupta, Madhavan, Sehgal, Nair, Mahajan et al., Extrapulmonary Manifestations of COVID-19, Nat. Med, doi:10.1038/s41591-020-0968-3
Guzzo, Furtek, Porras, Chen, Tipping et al., Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects, J. Clin. Pharmacol, doi:10.1177/009127002237994
Huertas, Montani, Savale, Pichon, Tu et al., Endothelial Cell Dysfunction: A Major Player in SARS-CoV-2 Infection (COVID-19)?, Eur. Respir. J, doi:10.1183/13993003.01634-2020
Hysi, Saha, Kolios, Photoacoustic Ultrasound Spectroscopy for Assessing Red Blood Cell Aggregation and Oxygenation, J. Biomed. Opt, doi:10.1117/1.JBO.17.12.125006
Kell, Laubscher, Pretorius, A Central Role for Amyloid Fibrin Microclots in Long COVID/PASC: Origins and Therapeutic Implications, Biochem. J, doi:10.1042/BCJ20220016
Kibria, Hysi, Strohm, Kolios, Identification of Red Blood Cell Rouleaux Formation Using Photoacoustic Ultrasound Spectroscopy
Klotz, Ogbuokiri, Okonkwo, Ivermectin Binds Avidly to Plasma Proteins, Eur. J. Clin. Pharmacol, doi:10.1007/BF00316107
Klykov, Van Der Zwaan, Heck, Meijer, Scheltema, Missing Regions within the Molecular Architecture of Human Fibrin Clots Structurally Resolved by XL-MS and Integrative Structural Modeling, Proc. Natl. Acad. Sci, doi:10.1073/pnas.1911785117
Kollman, Pandi, Sawaya, Riley, Doolittle, Crystal Structure of Human Fibrinogen, Biochemistry, doi:10.1021/bi802205g
Lakhdari, Tabet, Boudraham, Laoussati, Aissanou et al., Red Blood Cells Injuries and Hypersegmented Neutrophils in COVID-19 Peripheral Blood Film, doi:10.1101/2020.07.24.20160101
Levi, Thachil, Iba, Levy, Coagulation Abnormalities and Thrombosis in Patients with COVID-19, Lancet Haematol, doi:10.1016/S2352-3026(20)30145-9
Li, Duan, Song, Xu, Comparative Study on the Interaction between Fibrinogen and Flavonoids, J. Mol. Struct, doi:10.1016/j.molstruc.2022.132963
Litvinov, Pieters, De Lange-Loots, Weisel, Fibrinogen, Macromolecular Protein Complexes III: Structure and Function
Liu, Tang, Pei, Zhang, Liu et al., Gastrodin Interaction with Human Fibrinogen: Anticoagulant Effects and Binding Studies, Chem. Eur. J, doi:10.1002/chem.200600549
Magro, Mulvey, Berlin, Nuovo, Salvatore et al., Complement Associated Microvascular Injury and Thrombosis in the Pathogenesis of Severe COVID-19 Infection: A Report of Five Cases, Transl. Res, doi:10.1016/j.trsl.2020.04.007
Marini, Gattinoni, Management of COVID-19 Respiratory Distress, JAMA, doi:10.1001/jama.2020.6825
Meiselman, Red Blood Cell Aggregation: 45 Years Being Curious, Biorheology, doi:10.3233/BIR-2009-0522
Melkumyants, Buryachkovskaya, Lomakin, Antonova, Serebruany, Mild COVID-19 and Impaired Blood Cell-Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?, Thromb. Haemost, doi:10.1055/a-1551-9911
Menter, Haslbauer, Nienhold, Savic, Hopfer et al., Postmortem Examination of COVID-19 Patients Reveals Diffuse Alveolar Damage with Severe Capillary Congestion and Variegated Findings in Lungs and Other Organs Suggesting Vascular Dysfunction, Histopathology, doi:10.1111/his.14134
Molyneux, Ward, Reflections on the Nobel Prize for Medicine 2015-The Public Health Legacy and Impact of Avermectin and Artemisinin, Trends Parasitol, doi:10.1016/j.pt.2015.10.008
Mondal, Lahiri, Deb, Bandyopadhyay, Shome et al., COVID-19: Are We Dealing with a Multisystem Vasculopathy in Disguise of a Viral Infection?, J. Thromb. Thrombolysis, doi:10.1007/s11239-020-02210-8
Navarro, Camprubí, Requena-Méndez, Buonfrate, Giorli et al., Safety of High-Dose Ivermectin: A Systematic Review and Meta-Analysis, J. Antimicrob. Chemother, doi:10.1093/jac/dkz524
O'boyle, Banck, James, Morley, Vandermeersch et al., Open Babel: An Open Chemical Toolbox, J. Cheminform, doi:10.1186/1758-2946-3-33
Ogata, Maley, Wu, Gilboa, Norman et al., Ultra-Sensitive Serial Profiling of SARS-CoV-2 Antigens and Antibodies in Plasma to Understand Disease Progression in COVID-19 Patients with Severe Disease, doi:10.1093/clinchem/hvaa213
Patterson, Francisco, Yogendra, Long, Pise et al., Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection, doi:10.3389/fimmu.2021.746021
Picken, Fibrinogen Amyloidosis, The Clot Thickens! Blood, doi:10.1182/blood-2009-12-236810
Preto, Gentile, Assessing and improving the performance of consensus docking strategies using the DockBox package, J Comput. Aided Mol. Des, doi:10.1007/s10822-019-00227-7
Pretorius, Venter, Laubscher, Kotze, Oladejo et al., Prevalence of Symptoms, Comorbidities, Fibrin Amyloid Microclots and Platelet Pathology in Individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC), Cardiovasc. Diabetol, doi:10.1186/s12933-022-01579-5
Pretorius, Venter, Laubscher, Lourens, Steenkamp et al., Prevalence of Readily Detected Amyloid Blood Clots in 'Unclotted' Type 2 Diabetes Mellitus and COVID-19 Plasma: A Preliminary Report
Price, Mccabe, Garfield, Wort, Thrombosis and COVID-19 Pneumonia: The Clot Thickens! Eur, Respir. J, doi:10.1183/13993003.01608-2020
Prize, The 2015 Nobel Prize in Physiology or Medicine-Press Release
Rapkiewicz, Mai, Carsons, Pittaluga, Kleiner et al., Megakaryocytes and Platelet-Fibrin Thrombi Characterize Multi-Organ Thrombosis at Autopsy in COVID-19: A Case Series, doi:10.1016/j.eclinm.2020.100434
Ryu, Sozmen, Dixit, Montano, Matsui et al., SARS-CoV-2 Spike Protein Induces Abnormal Inflammatory Blood Clots Neutralized by Fibrin Immunotherapy, doi:10.1101/2021.10.12.464152
Sabioni, De Lorenzo, Lamas, Muccillo, Castro-Faria-Neto et al., Systemic Microvascular Endothelial Dysfunction and Disease Severity in COVID-19 Patients: Evaluation by Laser Doppler Perfusion Monitoring and Cytokine/Chemokine Analysis, Microvasc. Res, doi:10.1016/j.mvr.2020.104119
Santin, Scheim, Mccullough, Yagisawa, Borody et al., A Multifaceted Drug of Nobel Prize-Honored Distinction with Indicated Efficacy against a New Global Scourge, COVID-19, New Microbes New Infect, doi:10.1016/j.nmni.2021.100924
Scheim, Deadly Embrace, Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody. Int. J. Mol. Sci, doi:10.3390/ijms23052558
Schneidman-Duhovny, Inbar, Nussinov, Wolfson, PatchDock and SymmDock: Servers for Rigid and Symmetric Docking, Nucleic Acids Res, doi:10.1093/nar/gki481
Shafreen, Lakshmi, Pandian, Park, Kim et al., Unraveling the Antioxidant, Binding and Health-Protecting Properties of Phenolic Compounds of Beers with Main Human Serum Proteins: In Vitro and In Silico Approaches, Molecules, doi:10.3390/molecules25214962
Singh, Joseph, Heerdt, Cullinan, Lutchmansingh et al., Persistent Exertional Intolerance After COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing, Chest, doi:10.1016/j.chest.2021.08.010
Soga, Shirai, Kobori, Hirayama, Use of Amino Acid Composition to Predict Ligand-Binding Sites, J. Chem. Inf. Model, doi:10.1021/ci6002202
Soriano, Murthy, Marshall, Relan, Diaz, A Clinical Case Definition of Post-COVID-19 Condition by a Delphi Consensus, Lancet Infect. Dis, doi:10.1016/S1473-3099(21)00703-9
Stubbs, Oschkinat, Mayr, Huber, Angliker et al., The Interaction of Thrombin with Fibrinogen. A structural basis for its specificity, Eur. J. Biochem, doi:10.1111/j.1432-1033.1992.tb16916.x
Swank, Senussi, Manickas-Hill, Yu, Li et al., Persistent Circulating SARS-CoC-2 Spike Is Associated with Post-Acute COVID-19 Sequelae, Clin. Infect. Dis, doi:10.1093/cid/ciac722
Syahbanu, Giriwono, Tjandrawinata, Suhartono, Molecular Docking of Subtilisin K2, a Fibrin-Degrading Enzyme from Indonesian Moromi, with Its Substrates, Food Sci. Technol. 2022, doi:10.1590/fst.61820
Valdés-Tresanco, Valdés-Tresanco, Valiente, Moreno, AMDock: A Versatile Graphical Tool for Assisting Molecular Docking with Autodock Vina and Autodock4, Biol. Direct, doi:10.1186/s13062-020-00267-2
Wagner, Steffen, Svetina, Aggregation of Red Blood Cells: From Rouleaux to Clot Formation, Comptes Rendus Phys, doi:10.1016/j.crhy.2013.04.004
Weisel, The Mechanical Properties of Fibrin for Basic Scientists and Clinicians, Biophys. Chem, doi:10.1016/j.bpc.2004.07.029
Wool, Miller, The Impact of COVID-19 Disease on Platelets and Coagulation, Pathobiology, doi:10.1159/000512007
Wygrecka, Birnhuber, Seeliger, Michalick, Pak et al., Altered Fibrin Clot Structure and Dysregulated Fibrinolysis Contribute to Thrombosis Risk in Severe COVID-19, Blood Adv, doi:10.1182/bloodadvances.2021004816
Yakovlev, Gorlatov, Ingham, Medved, Interaction of Fibrin(Ogen) with Heparin: Further Characterization and Localization of the Heparin-Binding Site, Biochemistry, doi:10.1021/bi0344073
Zhmurov, Protopopova, Litvinov, Zhukov, Weisel et al., Atomic Structural Models of Fibrin Oligomers, Structure, doi:10.1016/j.str.2018.04.005