Abstract
The world is currently facing a novel coronavirus (SARS-CoV-2) pandemic. The greatest threat that is disrupting the normal functioning of society is the exceptionally high species independent transmission. Drug repurposing is understood to be the best strategy to immediately deploy well-characterized agents against new pathogens. Several repurposable drugs are already in evaluation for determining suitability to treat COVID-19. One such promising compound includes heparin, which is widely used in reducing thrombotic events associated with COVID-19 induced pathology. As part of identifying target-specific antiviral compounds among FDA and world-approved libraries using high-throughput virtual screening (HTVS), we previously evaluated top hits for anti-SARS-CoV-2 activity. Here, we report results of highly efficacious viral entry blocking properties of heparin (IC50 = 12.3 nM) in the complete virus assay, and further, propose ways to use it as a potential transmission blocker. Exploring further, our in-silico analysis indicated that the heparin interacts with post-translational glycoconjugates present on spike proteins. The patterns of accessible spike-glycoconjugates in open and closed states are completely contrasted by one another. Heparin-binding to the open conformation of spike structurally supports the state and may aid ACE2 binding as reported with cell surface-bound heparan sulfate. We also studied spike protein mutant variants’ heparin interactions for possible resistance. Based on available data and optimal absorption properties by the skin, heparin could potentially be used to block SARS-CoV-2 transmission. Studies should be designed to exploit its nanomolar antiviral activity to formulate heparin as topical or inhalation-based formulations, particularly on exposed areas and sites of primary viremia e.g. ACE2 rich epithelia of the eye (conjunctiva/lids), nasal cavity, and mouth.
【저자키워드】 severe acute respiratory syndrome coronavirus 2, Coronavirus disease 2019, angiotensin-converting enzyme 2, Receptor binding domain, Neuropilin-1, United States, transmembrane serine protease 2, Low-molecular-weight heparin, Protein Data Bank, COVID-19coronavirus disease 2019, SARS-CoV-2severe acute respiratory syndrome coronavirus 2, PDBProtein Data Bank, RBDReceptor Binding Domain, CDCCenters for Disease Control and Prevention, Centers for Disease Control and Prevention, identity, ACE2angiotensin-converting enzyme 2, UFHunfractionated heparin, unfractionated heparin, TMPRSS2transmembrane serine protease 2, FDAU.S. Food and Drug Administration, U.S. Food and Drug Administration, PBSphosphate-buffered saline, phosphate-buffered saline, FBSfetal bovine serum, fetal bovine serum, P/Spen strep, pen strep, NRP1neuropilin-1, EMEMEagle's Minimum Essential Medium, Eagle's Minimum Essential Medium, LMWHlow-molecular-weight heparin, HTVShigh throughput virtual screening, high throughput virtual screening, IDidentity, 【초록키워드】 COVID-19, Drug repurposing, SARS-CoV-2, pathology, ACE2, pandemic, variant, Transmission, nasal, Virtual screening, drug, antiviral activity, FDA, viral entry, IC50, Spike protein, Novel coronavirus, SARS-CoV-2 transmission, Viremia, Pathogens, mutant, in-silico, Interaction, Anti-SARS-CoV-2 Activity, Analysis, Spike proteins, ACE2 binding, Support, available data, treat, potential transmission, epithelia, Complete, Antiviral compound, Cell, independent, thrombotic event, include, reported, indicated, evaluated, reducing, interact, disrupting, virus assay, with COVID-19, 【제목키워드】 Efficacy, SARS-CoV-2 transmission, In-vitro, Prevent,