Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses

Artese, Anna; Svicher, Valentina; Costa, Giosuè; Salpini, Romina; Maio, V.C. Di; Alkhatib, Mohammad; Ambrosio, Francesca Alessandra; Santoro, Maria Mercedes; Assaraf, Yehuda G.; Alcaro, Stefano; Ceccherini‐Silberstein, Francesca

doi:10.1016/j.drup.2020.100721

Cited by 91 publications

(81 citation statements)

References 155 publications

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“…Patient sequences all belonged to clade 20B, corresponding to lineage B.1.1. According to literature data, [18][19][20][21][22][23][24][25] no mutations related to possible resistance to remdesivir were observed, also as minority variant when considering a cut off of 1%.…”

Section: Case Historymentioning

confidence: 97%

The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient – a case study

Sepulcri

Dentone

Mikulska

et al. 2021

Preprint

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BackgroundImmunocompromised patients show prolonged shedding of SARS-CoV-2 in nasopharyngeal swabs. We report a case of a prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of COVID-19 in a lymphoma patient.MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by Real time-PCR (RT-PCR). On five positive nasopharyngeal swabs, we performed viral culture and next generation sequencing. We analysed the patients’ adaptive and innate immunity to characterize T and NK cell subsets.FindingsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive with cycle threshold mean values of 22 ± 1·3 for over 8 months. All five performed viral cultures were positive and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in three out of four COVID-19 clinical relapses and cleared each time after remdesivir treatment. T and NK cells dynamic was different in aviremic and viremic samples and no SARS-CoV-2 specific antibodies were detected throughout the disease course.InterpretationIn our patient, SARS-CoV-2 persisted with proven infectivity for over eight months. Viremia was associated with COVID-19 relapses and remdesivir treatment was effective in viremia clearance and symptoms remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood that are probably recruited in inflammatory tissue for viral eradication. In addition we found a high level of NK cells repertoire perturbation with a relevant involvement during SARS-CoV-2 viremia.FundingNone.

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Section: Case Historymentioning

confidence: 97%

The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient – a case study

Sepulcri

Dentone

Mikulska

et al. 2021

Preprint

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“…Many clinical strategies to inhibit viral replication and release involve the use of repurposed antivirals ( Artese et al, 2020 ; Drożdżal et al, 2020 ; Pawar, 2020 ). Drugs that have been under study for potential uses in COVID-19 include remdesivir, a broad-spectrum RdRp inhibitor that was previously studied for Ebola treatment, and favipiravir (obtained conditional marketing approval in Japan for the treatment of influenza), and the approved HIV protease inhibitor combination lopinavir/ritonavir ( Beigel et al, 2020 ; Furuta et al, 2017 ; Grein et al, 2020 ; McMahon et al, 2020 ; Sheahan et al, 2017 ; Wang et al, 2020b ).…”

Section: Repurposing Of Existing Drugs For Covid-19mentioning

confidence: 99%

“…The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to spread across the globe ( Artese et al, 2020 ). The majority of people who become infected with SARS-CoV-2 experience mild to moderate respiratory illness.…”

Section: Introductionmentioning

confidence: 99%

“…There are currently no approved vaccines or therapeutics for COVID-19, though many potential treatments are being evaluated in ongoing clinical trials. These include repurposing the existing drugs previously approved for other conditions, as well as novel biological products that are designed to target the key checkpoints in the SARS-CoV-2 lifecycle ( Artese et al, 2020 ; Drożdżal et al, 2020 ). To facilitate COVID-19 drug development, the US Food and Drug Administration (FDA) has created a special emergency program for possible coronavirus therapies, the Coronavirus Treatment Acceleration Program (CTAP) ( U.S. Food and Drug Administration, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

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COVID-19 update: The race to therapeutic development

Twomey

Luo

Dean

et al. 2020

Drug Resistance Updates

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health. At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide. Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S. National Library of Medicine (clinicaltrials.gov), results that can clarify benefits and risks of candidate therapies are only gradually becoming available. We herein describe recent advances in understanding SARS-COV-2 pathobiology and potential therapeutic targets that are involved in viral entry into host cells, viral spread in the body, and the subsequent COVID-19 progression. We highlight two major lines of therapeutic strategies for COVID-19 treatment: 1) repurposing the existing drugs for use in COVID-19 patients, such as antiviral medications (e.g., remdesivir) and immunomodulators (e.g., dexamethasone) which were previously approved for other disease conditions, and 2) novel biological products that are designed to target specific molecules that are involved in SARS-COV-2 viral entry, including neutralizing antibodies against the spike protein of SARS-COV-2, such as REGN-COV2 (an antibody cocktail) and LY-COV555, as well as recombinant human soluble ACE2 protein to counteract SARS-COV-2 binding to the transmembrane ACE2 receptor in target cells. Finally, we discuss potential drug resistance mechanisms and provide thoughts regarding clinical trial design to address the diversity in COVID-19 clinical manifestation. Of note, preventive vaccines, cell and gene therapies are not within the scope of the current review.

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“…The 3-chymotrypsin-like protease (3CL-PR) and the RNA-dependent-RNA polymerase (RdRp) were also suggested to be druggable targets. 45 Inhibiting the main viral protease is a strategy that has been explored extensively to develop treatments for other viruses such as hepatitis C virus (HCV) and human immunodeficient virus (HIV) 46 and that could yield promising treatments against COVID-19 as well. 47 The general mechanism of action of viral proteases is fairly well-understood 48 and that of SARS-CoV-2's main protease has been uncovered recently via multiscale molecular modelling, 49 which could boost the development of specific therapeutics significantly in the near future.…”

Section: Introductionmentioning

confidence: 99%

Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

Marion¹,

Marion

2020

Preprint

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<p>Spike glycoprotein (S), one of the signature proteins of the SARS-CoV-2, initiates the membrane fusion and virus entry to the host cell. The S protein’s key role in virus viability makes it an attractive candidate for drug design studies. Besides the recent structural characterization of the S protein, information fundamental to drug design such as possible binding sites or molecular fragments with high affinity towards the protein is unknown. We explored the druggability of this protein, focusing on its S1 and S2 domains. We performed virtual screening studies on both closed and open forms of the protein, using both cryo-EM structures and geometries obtained from molecular dynamic simulations. We targeted 20 distinct ligand binding centres with a set of about 9,000 molecules. Our docking calculations followed by molecular mechanics-based refinement of ligand/protein complexes led us to detect eight binding sites that were so far undocumented. By further focusing on a subset of approximately 1,000 approved and marketed drugs, we aimed at suggesting a new direction for drug repurposing strategies that were not considered so far. Within this approved set, our best hits include a number of antibacterial and antiviral drugs (e.g., Streptomycin, Nelfinavir), which were not yet investigated clinically in treating COVID-19. We also identified some molecules (e.g., folic acid, Famotidine) that were already suggested to be effective towards SARS-CoV-2, yet without molecular explanation. Our results also indicate a great affinity of SARS-CoV-2’s S protein towards nucleoside analogues, either approved or experimental.</p>

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Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses

Cited by 91 publications

References 155 publications

The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient – a case study

The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient – a case study

COVID-19 update: The race to therapeutic development

Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

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