A possible strategy to fight COVID-19: Interfering with spike glycoprotein trimerization

Bongini, Pietro; Trezza, Alfonso; Bianchini, Monica; Spiga, Ottavia; Niccolai, Neri

doi:10.1016/j.bbrc.2020.04.007

Cited by 29 publications

(31 citation statements)

References 14 publications

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“…The trimer-binding interface between individual S protomers and the interaction sites of trimerization are not fully characterized for the SARS-CoV-2. Recent studies have suggested several residues that contribute to the formation or to stabilize the S trimeric structure; and most of them are located at the S2 subunit (mainly in the S2-NTD, FP, CR, HR1, CH and CD) [53] , [54] , [55] , [56] , [57] , [58] . Thirteen of these residues (E702, Y707, N709, N710, Y789, K790, K795, F797, G798, T859, G891, Q895, F898) are described by multiple authors and represent CDR or T-RHS for drug targeting highlighted in our study [53] , [54] , [55] , [56] , [57] , [58] .…”

Section: Resultsmentioning

confidence: 99%

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

Trigueiro-Louro

Correia

Figueiredo-Nunes

et al. 2020

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

Trigueiro-Louro

Correia

Figueiredo-Nunes

et al. 2020

Computational and Structural Biotechnology Journal

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“…Another approach could be to target viral assembly. The formation of the S spike trimer might not be a fast and direct process, so there is a chance to block the quaternary structure of the spike ( Bongini et al, 2020 ). Analysis of protein-protein interfaces of the spike has led to the prediction of ligands (Ergoloid, Darifenacin, 5-methyl-tetrahydrofolic acid, Buclizine, Saquinavir, Solifenacin, Sorafenib, tetrahydrofolic acid) that potentially could affect this process ( Bongini et al, 2020 ).…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Drug Weaponry to Fight Against SARS-CoV-2

Cabezón

Aréchaga

2020

Front. Mol. Biosci.

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The current outbreak of SARS-CoV-2 virus has caused a large increase in mortality and morbidity associated with respiratory diseases. Huge efforts are currently ongoing to develop a vaccine against this virus. However, alternative approaches could be considered in the fight against this disease. Among other strategies, structural-based drug design could be an effective approach to generate specific molecules against SARS-CoV-2, thus reducing viral burden in infected patients. Here, in addition to this structural approach, we also revise several therapeutic strategies to fight against this viral threat. Furthermore, we report ACE-2 genetic polymorphic variants affecting residues involved in close contacts with SARS-CoV-2 that might be associated to different infection risks. These analyses could provide valuable information to predict the course of the disease.

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“…S glycoprotein is highly immunogenic, and it is a promising target for drug design 11 . We showed that a combination of four 20-mer synthetic peptides disrupting SARS-CoV S heterotrimer reduced or completely inhibited infectivity in vitro 12 .…”

Section: Introductionmentioning

confidence: 99%

An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

Trezza

Iovinelli

Santucci

et al. 2020

Sci Rep

Self Cite

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The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein-ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptorbinding domain of the Spike protein with high affinity and prevent ACE2 interaction. The World Health Organisation (WHO) declared the Coronavirus disease (COVID-19) outbreak a pandemic on March 12th 2020, and as of May 21st, over 4,893,186 cases and 323,256 deaths have been reported (https :// www.who.int/emerg encie s/disea ses/novel-coron aviru s-2019/situa tion-repor ts/). The Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was identified as the viral agent causing the disease. SARS-CoV-2 is closely related to the SARS-CoV, which caused a pandemic in 2002-2003 1 , and it is believed to be the third member of the Coronaviridae family to cause severe respiratory diseases in human 2. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. SARS-CoV-2 has a single-stranded positive-sense RNA composed of 29,903 nt containing five genes, ORF1ab (codifying 16 non-structural proteins), spike (S), envelope (E), membrane (M) and nucleocapsid (N) genes 3. The virus uses the S homotrimeric glycoprotein located on the virion surface to allow entry into the human cells 4. The S protein goes through major structural rearrangements to mediate viral and human cell membranes fusion. The process is initiated by the binding of the receptor-binding domain (RBD) of the S1 subunit to the peptidase domain (PD) of angiotensin-converting enzyme 2 receptor (ACE2) on the host cell 5. Structural studies have shown that two S protein trimers can simultaneously bind to one ACE2 dimer 6. This induces a conformational change that expose a proteolytic site on the S protein, which is cleaved by the cellular serine protease TMPRSS2 7. Dissociation of S1 induces transition of the S2 subunit to a post fusion conformation, with exposed fusion peptides 8 , which allows endocytic entry of virus 9. Wrapp et ...

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A possible strategy to fight COVID-19: Interfering with spike glycoprotein trimerization

Cited by 29 publications

References 14 publications

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

Drug Weaponry to Fight Against SARS-CoV-2

An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

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