Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent
Antonio Francés-Monerris, Cristina García-Iriepa, Isabel Iriepa, Cécilia Hognon, Tom Miclot, Giampaolo Barone, Antonio Monari, Marco Marazzi
The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research 2020, 178, 104787) show a potent inhibition of SARS-CoV-2 replication in vitro by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL pro and PL pro , and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host-and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.
Entry for the Table of Contents Molecular dynamics reveal the interaction hotspots between the antiparasitic drug ivermectin and several SARS-CoV-2 structures. These findings suggest a novel dual mechanism of action for this drug, in which both host-directed and virus-directe effects act synergistically to stop SARS-CoV-2 infection.
References
Bedford, Enria, Giesecke, Heymann, Ihekweazu et al., COVID-19: towards controlling of a pandemic, Lancet
Bray, Rayner, Noël, Jans, Wagstaff, Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses, Antiviral Res
Báez-Santos, Mielech, Deng, Baker, Mesecar, Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus, J. Virol
Báez-Santos, St, John, Mesecar, The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds, Antiviral Res
Békés, Ekkebus, Ovaa, Huang, Lima, Recognition of Lys48-linked di-ubiquitin and deubiquitinating activities of the SARS coronavirus papain-like protease, Mol. Cell
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Dasgupta, Sen, Bakshi, Dasgupta, Manna et al., Nsp7 and Spike Glycoprotein of SARS-CoV-2 are envisaged as Potential Targets of Vitamin D and Ivermectin
Elmezayen, Al-Obaidi, Şahin, Yelekçi, Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes, J. Biomol. Struct. Dyn
Florindo, Kleiner, Vaskovich-Koubi, Acúrcio, Carreira et al., Immune-mediated approaches against COVID-19, Nat. Nanotechnol
Folegatti, Ewer, Aley, Angus, Becker et al., Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial, Lancet
Galindo-Murillo, Robertson, Zgarbová, Šponer, Otyepka et al., Assessing the Current State of Amber Force Field Modifications for DNA, J. Chem. Theory Comput
Garcia-Iriepa, Hognon, Francés-Monerris, Iriepa, Miclot et al., Thermodynamics of the Interaction Between SARS-CoV-2 Spike Protein and Human ACE2 Receptor. Effects of Possible Ligands
Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing, bioRxiv
Hognon, Miclot, Iriepa, Francés-Monerris, Grandemange et al., Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses, J. Phys. Chem. Lett
Hopkins, Le Grand, Walker, Roitberg, Long-time-step molecular dynamics through hydrogen mass repartitioning, J. Chem. Theory Comput
Humphrey, Dalke, Schulten, VMD: Visual molecular dynamics, J. Mol. Graph
Huynh, Wang, Luan, Silico Exploration of Molecular Mechanism of Clinically Oriented Drugs for Possibly Inhibiting SARS-CoV-2's Main Protease, J. Phys. Chem. Lett
Islam, Parves, Paul, Uddin, Rahman et al., A Molecular Modeling Approach to Identify Effective Antiviral Phytochemicals against the Main Protease of SARS-CoV-2, J. Biomol. Struct. Dyn
Ivani, Dans, Noy, Pérez, Faustino et al., PARMBSC1: A refined force-field for DNA simulations, Nat. Methods
Jorgensen, Chandrasekhar, Madura, Impey, Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys
Khan, Ali, Wang, Irfan, Khan et al., Marine natural compounds as potents inhibitors against the main protease of SARS-CoV-2. A molecular dynamic study, J. Biomol. Struct. Dyn
Kilic, Weissleder, Lee, Molecular and immunological diagnostic tests of COVID-19 -current status and challenges
Kumar, Jeyaraman, Jain, Anudeep, A Wonder Drug in the Arsenal against COVID-19: Medication Evidence from Ivermectin, J. Adv. Med. Med. Res
Kusov, Tan, Alvarez, Enjuanes, Hilgenfeld, A G-quadruplex-binding macrodomain within the "SARSunique domain" is essential for the activity of the SARS-coronavirus replication-transcription complex, Virology
Lai, Hanchapola, Steer, Smith, Angiotensin-converting enzyme 2 ectodomain shedding cleavagesite identification: Determinants and constraints, Biochemistry
Lan, Ge, Yu, Shan, Zhou et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature
Lehrer, Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2
Lei, Kusov, Hilgenfeld, Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein, Antiviral Res
Macchiagodena, Pagliai, Andreini, Rosato, Procacci, Upgrading and Validation of the AMBER Force Field for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with Four Protein Ligands, J. Chem. Inf. Model
Macchiagodena, Pagliai, Procacci, Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling, Chem. Phys. Lett
Mahanta, Chowdhury, Gogoi, Goswami, Borah et al., Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach, J. Biomol. Struct. Dyn
Maier, Martinez, Kasavajhala, Wickstrom, Hauser et al., ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB, J. Chem. Theory Comput
Maurya, A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients
Peña-Silva, Duffull, Steer, Jaramillo-Rincon, Gwee et al., Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19, Br. J. Clin. Pharmacol
Phillips, Braun, Wang, Gumbart, Tajkhorshid et al., Scalable molecular dynamics with NAMD, J. Comput. Chem
Prabakaran, Xiao, Dimitrov, A model of the ACE2 structure and function as a SARS-CoV receptor, Biochem. Biophys. Res. Commun
Rajter, Sherman, Fatteh, Vogel, Sacks et al., ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19, medRxiv
Ramos-Guzmán, Ruiz-Pernía, Tuñón, Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods
Ratia, Kilianski, Baez-Santos, Baker, Mesecar, Structural basis for the ubiquitin-linkage specificity and deISGylating activity of SARS-CoV papain-like protease, PLoS Pathog
Ratia, Pegan, Takayama, Sleeman, Coughlin et al., A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication, Proc. Natl. Acad. Sci
Shang, Ye, Shi, Wan, Luo et al., Structural basis of receptor recognition by SARS-CoV-2, Nature
Sharun, Dhama, Patel, Pathak, Tiwari et al., Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19, Ann. Clin. Microbiol. Antimicrob
Sk, Roy, Jonniya, Poddar, Kar, Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations, J. Biomol. Struct. Dyn
Tan, Vonrhein, Smart, Bricogne, Bollati et al., The SARS-Unique Domain (SUD) of SARS coronavirus contains two macrodomains that bind G-quadruplexes, PLoS Pathog
Trott, Olson, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem
Tu, Chien, Yarmishyn, Lin, Luo et al., A Review of SARS-CoV-2 and the Ongoing Clinical Trials, Int. J. Mol. Sci
Wang, Wolf, Caldwell, Kollman, Case, Development and testing of a general amber force field, J. Comput. Chem
Wang, Zhang, Wu, Niu, Song et al., Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2, Cell
Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2, Science
Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Res
Yang, Yang, Ding, Liu, Lou et al., The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor, Proc. Natl. Acad. Sci
Zgarbová, Šponer, Otyepka, Cheatham, Galindo-Murillo et al., Refinement of the Sugar-Phosphate Backbone Torsion Beta for AMBER Force Fields Improves the Description of Z-and B-DNA, J. Chem. Theory Comput
Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors, Science
Świderek, Moliner, Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 Mpro by QM/MM computational methods, Chem. Sci
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