Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
Jacques Fantini, Coralie Di Scala, Henri Chahinian, Nouara Yahi
International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.105960
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References
Colson, Rolain, Raoult, Chloroquine for the 2019 novel coronavirus SARS-CoV-2, Int J Antimicrob Agents
Fantini, Garmy, Yahi, Prediction of glycolipid-binding domains from the amino acid sequence of lipid raft-associated proteins: application to HpaA, a protein involved in the adhesion of Helicobacter pylori to gastrointestinal cells, Biochemistry
Fantini, Yahi, Brain lipids in synaptic function and neurological disease. Clues to innovative therapeutic strategies for brain disorders
Fantini, Yahi, Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases, Expert Rev Mol Med
Flores, Ramirez-Franco, Desplantes, Debreux, Ferracci et al., Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B, Proc Natl Acad Sci
Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends,
doi:10.5582/bst.2020.01047
Guvench, Greene, Kamath, Brady, Venable et al., Additive empirical force field for hexopyranose monosaccharides, J Comput Chem
Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052
Huang, Huang, Scala, Wang, Wandall et al., The glycosphingolipid MacCer promotes synaptic bouton formation in drosophila by interacting with Wnt, Elife
Huta, Mehlenbacher, Nie, Lai, Zubieta et al., The lysosomal protein saposin B binds chloroquine, Chem Med Chem
Lee, Patel, Ståhle, Park, Kern et al., CHARMM-GUI membrane builder for complex biological membrane simulations with glycolipids and lipoglycans, J Chem Theory Comput
Li, Hulswit, Widjaja, Raj, Mcbride et al., Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein, Proc Natl Acad Sci
Li, Moore, Vasilieva, Sui, Wong et al., Angiotensinconverting enzyme 2 is a functional receptor for the SARS coronavirus, Nature
Lu, Liu, Tam, Lipid rafts are involved in SARS-CoV entry into Vero E6 cells, Biochem Biophys Res Commun
Mahfoud, Garmy, Maresca, Yahi, Puigserver et al., Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins, J Biol Chem
Matrosovich, Herrler, Klenk, Sialic acid receptors of viruses, Top Curr Chem
Mauthe, Orhon, Rocchi, Zhou, Luhr et al., Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion, Autophagy
Mullard, Drug repurposing programmes get lift off, Nat Rev Drug Discov
Park, Walls, Wang, Sauer, Li et al., Structures of MERS-CoV spike glycoprotein in complex with sialoside attachment receptors, Nat Struct Mol Biol
Savarino, Trani, Donatelli, Cauda, Cassone, New insights into the antiviral effects of chloroquine, Lancet Infect Dis
Scala, Fantini, Hybrid in silico/in vitro approaches for the identification of functional cholesterol-binding domains in membrane proteins, Methods Mol Biol
Tortorici, Walls, Lang, Wang, Li et al., Structural basis for human coronavirus attachment to sialic acid receptors, Nat Struct Mol Biol
Verma, Gupta, Lal, Host lipid rafts play a major role in binding and endocytosis of influenza A virus, Viruses
Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science
Yahi, Fantini, Deciphering the glycolipid code of Alzheimer's and Parkinson's amyloid proteins allowed the creation of a universal ganglioside-binding peptide, PLoS One
Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2, Science,
doi:10.1126/science.abb2762
Yao, Ye, Zhang, Cui, Huang et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
doi:10.1093/cid/ciaa237
Zhou, Yang, Wang, Hu, Zhang et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
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