Your browser doesn't support javascript.
Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions.
Day, Christopher J; Bailly, Benjamin; Guillon, Patrice; Dirr, Larissa; Jen, Freda E-C; Spillings, Belinda L; Mak, Johnson; von Itzstein, Mark; Haselhorst, Thomas; Jennings, Michael P.
  • Day CJ; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Bailly B; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Guillon P; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Dirr L; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Jen FE; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Spillings BL; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Mak J; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • von Itzstein M; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.
  • Haselhorst T; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia t.haselhorst@griffith.edu.au m.jennings@griffith.edu.au.
  • Jennings MP; Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia t.haselhorst@griffith.edu.au m.jennings@griffith.edu.au.
mBio ; 12(2)2021 03 30.
Article in English | MEDLINE | ID: covidwho-1522913
Semantic information from SemMedBD (by NLM)
1. angiotensin converting enzyme 2 PART_OF Homo sapiens
Subject
angiotensin converting enzyme 2
Predicate
PART_OF
Object
Homo sapiens
2. COVID-19 CAUSES Cessation of life
Subject
COVID-19
Predicate
CAUSES
Object
Cessation of life
3. Vero Cells LOCATION_OF Virus Replication
Subject
Vero Cells
Predicate
LOCATION_OF
Object
Virus Replication
4. Evans blue DISRUPTS Virus Replication
Subject
Evans blue
Predicate
DISRUPTS
Object
Virus Replication
5. lifitegrast DISRUPTS Virus Replication
Subject
lifitegrast
Predicate
DISRUPTS
Object
Virus Replication
6. lumacaftor DISRUPTS Virus Replication
Subject
lumacaftor
Predicate
DISRUPTS
Object
Virus Replication
7. angiotensin converting enzyme 2 PART_OF Homo sapiens
Subject
angiotensin converting enzyme 2
Predicate
PART_OF
Object
Homo sapiens
8. COVID-19 CAUSES Cessation of life
Subject
COVID-19
Predicate
CAUSES
Object
Cessation of life
9. Vero Cells LOCATION_OF Virus Replication
Subject
Vero Cells
Predicate
LOCATION_OF
Object
Virus Replication
10. Evans blue DISRUPTS Virus Replication
Subject
Evans blue
Predicate
DISRUPTS
Object
Virus Replication
11. lifitegrast DISRUPTS Virus Replication
Subject
lifitegrast
Predicate
DISRUPTS
Object
Virus Replication
12. lumacaftor DISRUPTS Virus Replication
Subject
lumacaftor
Predicate
DISRUPTS
Object
Virus Replication
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 µM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Virus Attachment / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: MBio.03681-20

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Virus Attachment / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: MBio.03681-20