TY - JOUR
T1 - Anti-fungal drug anidulafungin inhibits SARS-CoV-2 Spike induced syncytia formation by targeting ACE2-Spike protein interaction
AU - Ahamad, Shahzaib
AU - Ali, Hashim
AU - Secco, Ilaria
AU - Giacca, Mauro
AU - Gupta, Dinesh
N1 - Funding Information:
MG acknowledges the British Heart Foundation (BHF) Programme Grant RG/19/11/34633. DG and SA acknowledge the bioinformatics infrastructure grant to ICGEB by the Department of Biotechnology, Government of India (no. BT/PR40151/BTIS/137/5/2021). SA is a recipient of a Research Associate fellowship from the Indian Council of Medical Research (ICMR), India (2019–6039 File No. ISRM/11(83)/2019).
Publisher Copyright:
Copyright © 2022 Ahamad, Ali, Secco, Giacca and Gupta.
PY - 2022/3/25
Y1 - 2022/3/25
N2 - Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor via its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested in-vitro using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.
AB - Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor via its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested in-vitro using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.
KW - SARS-CoV-2
KW - COVID-19
KW - ACE2
KW - Virtual Screening and MD Simulations
KW - Syncytia
UR - http://www.scopus.com/inward/record.url?scp=85128312516&partnerID=8YFLogxK
U2 - 10.3389/fgene.2022.866474
DO - 10.3389/fgene.2022.866474
M3 - Article
SN - 1664-8021
VL - 13
JO - Frontiers of Genetics
JF - Frontiers of Genetics
M1 - 866474
ER -
