Heparin: A simplistic repurposing to prevent SARS-CoV-2 transmission in light of its in-vitro nanomolar efficacy

Autor: Andrew S. Herbert, Jawed Fareed, John M. Dye, Samantha E. Zak, Dawid Maciorowski, Yash Gupta, Prakasha Kempaiah, Chandrashekhar Vishwanath Kulkarni, Ravi Durvasula
Jazyk: angličtina
Rok vydání: 2021
Předmět:
P/S
pen strep
02 engineering and technology
Pharmacology
medicine.disease_cause
Biochemistry
United States
FDA
U.S. Food and Drug Administration
chemistry.chemical_compound
Structural Biology
EMEM
Eagle's Minimum Essential Medium
ID
identity
PDB
protein data bank
Repurposing
Coronavirus
COVID-19
coronavirus disease 2019
0303 health sciences
Anticoagulant
C100
General Medicine
Heparin
Heparan sulfate
021001 nanoscience & nanotechnology
Drug repositioning
Spike Glycoprotein
Coronavirus
Topical delivery
0210 nano-technology
medicine.drug
medicine.drug_class
PBS
phosphate-buffered saline
Spike protein
ACE2
angiotensin-converting enzyme 2
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Article
03 medical and health sciences
RBD
receptor binding domain
FBS
fetal bovine serum
Viral entry
Lipid-based formulations
medicine
Humans
UFH
unfractionated heparin
Molecular Biology
LMWH
low-molecular-weight heparin
030304 developmental biology
Virtual screening
SARS-CoV-2
Drug Repositioning
COVID-19
COVID-19 Drug Treatment
NRP1
neuropilin-1
chemistry
Sulfated polysaccharide
SARS-CoV2
TMPRSS2
transmembrane serine protease 2
Transmission-blocking
HTVS
high throughput virtual screening
CDC
centers for disease control and prevention
Zdroj: International Journal of Biological Macromolecules
ISSN: 0141-8130
Popis: 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 (IC = 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. [Abstract copyright: Copyright © 2018 Elsevier B.V. All rights reserved.]
Databáze: OpenAIRE
Externí odkaz: