SMALL MOLECULE INHIBITOR FOR BLOCKING SARS-CoV-2 ENTRY
Topics in Antiviral Medicine
; 31(2):215, 2023.
Article
in English
| EMBASE | ID: covidwho-2320550
ABSTRACT
Background:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel and highly pathogenic coronavirus and is the causative agent of COVID-19, an ongoing pandemic that has posed a serious threat to public health and global economy. Thus, there is a pressing need for therapeutic interventions that target essential viral proteins and regulate virus spread and replication. To invade the host cell, the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein binds to the host cell's ACE2 receptor, followed by cleavage events that allow the Spike protein to fuse with the host cell membrane. Thus, the essential role of Spike protein in ACE2 receptor binding and viral fusion makes it a prime target for therapeutic interventions. Method(s) We performed molecular docking and molecular dynamics (MD) simulation-based virtual screening against SARS-CoV-2 RBD/ACE2 interface using a commercial library of 93,835 drug-like compounds. Compounds with promising docking poses and scores were selected for further MD simulation refinement, from which ten lead compounds were identified. Antiviral potencies of ten lead compounds were evaluated against lentiviral vectors pseudotyped with SARS-CoV-2 Spike to down select to a single lead compound, SAI4. ELISA-based assays were employed to determine the binding affinities of SAI4 to recombinant SARS-CoV-2 RBD. Antiviral potential of SAI4 was validated against genuine SARS-CoV-2 in a BSL3 setting. Result(s) We identified SAI4 as a candidate small molecule, which inhibited SARS-CoV-2 pseudovirus entry with IC50 value of ~18 muM. We determined that SAI4 binds RDB with a Kd of ~20 muM. Using cells engineered to express ACE2 and cells that express physiological levels of ACE2, we found that SAI4 inhibited SARS-CoV-2 pseudovirus entry at both engineered and physiological ACE2 levels. We validated the antiviral potential of SAI4 against genuine SARS-CoV-2 and HCoV-NL63. Lastly, we demonstrated antiviral potential of SAI4 against four SARS-CoV-2 variants of concern (alpha, beta, gamma, and delta). Conclusion(s) Using virtual screening, we identified SAI4 as the promising hit compound which displayed inhibitory activities against SARS-CoV-2 entry and its four variants of concern. Thus, our study will pave the way for further development of small molecules for therapeutic targeting of SARS-CoV-2 entry to combat the COVID-19 pandemic.
binding affinity; conference abstract; controlled study; coronavirus disease 2019; enzyme linked immunosorbent assay; Human coronavirus NL63; ic50; molecular docking; molecular dynamics; nonhuman; pandemic; protein expression; protein function; receptor binding; SARS-CoV-2 pseudovirus; Severe acute respiratory syndrome coronavirus 2; spike; variant of concern; angiotensin converting enzyme 2; antivirus agent; endogenous compound; lentivirus vector; virus spike protein
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Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Topics in Antiviral Medicine
Year:
2023
Document Type:
Article
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