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Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective

MOLECULES (2022)

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Article Multidisciplinary Sciences

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Lihong Liu et al.

Summary: The B.1.1.529/Omicron variant of SARS-CoV-2, initially detected in southern Africa, has rapidly spread globally and is expected to become dominant due to its enhanced transmissibility in the coming weeks. This variant poses a threat to the efficacy of current COVID-19 vaccines and antibody therapies due to its significant antibody resistance. Even individuals who have received vaccines and booster doses may have reduced neutralizing activity against B.1.1.529.

NATURE (2022)

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Article Medicine, General & Internal

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

A. Jayk Bernal et al.

Summary: This study found that early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

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Letter Cell Biology

Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

Yao Zhao et al.

PROTEIN & CELL (2022)

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Review Immunology

Efficacy and safety of arbidol (umifenovir) in patients with COVID-19: A systematic review and meta-analysis

Behnam Amani et al.

Summary: Arbidol showed no significant benefit compared to non-antiviral treatment or other therapeutic agents in COVID-19 treatment, but demonstrated better efficacy compared to lopinavir/ritonavir. Further high-quality studies are needed to determine the efficacy and safety of arbidol for COVID-19.

IMMUNITY INFLAMMATION AND DISEASE (2021)

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Article Biochemistry & Molecular Biology

Clinical Antiviral Drug Arbidol Inhibits Infection by SARS-CoV-2 and Variants through Direct Binding to the Spike Protein

Anton Shuster et al.

Summary: Arbidol (ARB) has been identified as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein, making it one of the more promising drug candidates for COVID-19.

ACS CHEMICAL BIOLOGY (2021)

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Review Pharmacology & Pharmacy

A review of potential suggested drugs for coronavirus disease (COVID-19) treatment

Parastoo Tarighi et al.

Summary: The latest COVID-19 pandemic has no conventional treatment or vaccine, leading to investigations on the repositioning of existing drugs as potential therapeutic options. Many drugs are currently undergoing clinical trials for efficacy and safety in treating COVID-19.

EUROPEAN JOURNAL OF PHARMACOLOGY (2021)

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Review Chemistry, Medicinal

SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19

Ilaria Vicenti et al.

Summary: The current SARS-CoV-2 pandemic requires urgent prevention and treatment strategies. Repurposing drugs approved for other indications or successfully tested for safety and tolerability is an attractive strategy to quickly provide effective medication for severe cases. While vaccination is awaited, repurposed drugs could help treat severe cases, and improving knowledge of RdRp activity may aid in drug development for SARS-CoV-2 and future pandemics.

EXPERT OPINION ON THERAPEUTIC PATENTS (2021)

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Review Infectious Diseases

A review on favipiravir: the properties, function, and usefulness to treat COVID-19

Seyed MohammadReza Hashemian et al.

Summary: Favipiravir has broad-spectrum antiviral activity against single-stranded RNA viruses, good tolerability in humans, and a high barrier to resistance. However, high doses are required for efficient antiviral activity, it is teratogenic in pregnant women and associated with hyperuricemia, so drug administration should be carefully controlled. Investigating Favipiravir's antiviral prophylactic potency and searching for pro-drugs or analogs with improved activity and safety are crucial.

EXPERT REVIEW OF ANTI-INFECTIVE THERAPY (2021)

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Article Biochemistry & Molecular Biology

SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis

Armin Bayati et al.

Summary: SARS-CoV-2 uses spike glycoprotein for initial interaction with cell surface and undergoes clathrin-mediated endocytosis, transferring viral RNA to cell cytosol. Knockdown of clathrin heavy chain reduces viral infectivity, highlighting the importance of clathrin-mediated endocytosis in virus infectivity.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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Review Chemistry, Medicinal

Drug repurposing approach to combating coronavirus: Potential drugs and drug targets

Jimin Xu et al.

Summary: This review summarizes therapeutic targets for treating coronaviruses and focuses on existing small molecule drugs that have potential for repurposing in future coronavirus infections, as well as discussing clinical progress in developing small molecule drugs for COVID-19.

MEDICINAL RESEARCH REVIEWS (2021)

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Article Medicine, General & Internal

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

A. C. Kalil et al.

Summary: Combination treatment with baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Multidisciplinary Sciences

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Goran Kokic et al.

Summary: Remdesivir is the only FDA-approved drug for treating COVID-19 patients, working by inhibiting the RNA-dependent RNA polymerase (RdRp) of coronaviruses. It hinders RNA synthesis and impairs proofreading by the viral 3'-exonuclease, leading to a stalled replication process.

NATURE COMMUNICATIONS (2021)

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Article Critical Care Medicine

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial

Jordana B. Cohen et al.

Summary: The study aimed to evaluate the impact of continuing versus discontinuing renin-angiotensin system inhibitors on outcomes in patients admitted to hospital with COVID-19. Results showed that continuing these medications had no significant effects compared to discontinuation in patients with COVID-19.

LANCET RESPIRATORY MEDICINE (2021)

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Article Chemistry, Multidisciplinary

Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase

Fabian Bylehn et al.

Summary: This study examined the molecular interactions of Remdesivir, ribavirin, and favilavir, revealing that they all bind strongly at the active site but may act via slightly different mechanisms. Remdesivir showed similar binding interactions to the natural base adenine, suggesting a potential secondary mechanism where it destabilizes the protein complex and interactions with RNA strands.

ACS CENTRAL SCIENCE (2021)

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Review Medicine, General & Internal

Major Update: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points

Anjum S. Kaka et al.

Summary: The study suggests that remdesivir may not significantly reduce mortality in COVID-19 patients, but it likely improves the percentage of patients who recover and reduces serious harms. It may also result in a small decrease in the proportion of patients needing ventilation.

ANNALS OF INTERNAL MEDICINE (2021)

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Article Microbiology

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

Steven S. Good et al.

Summary: AT-527, an oral antiviral drug, has potent activity against various coronaviruses, including SARS-CoV-2. In vitro experiments have shown that AT-511 has high efficacy in inhibiting the replication of SARS-CoV-2, with minimal cytotoxicity. Studies suggest that AT-527 may be an effective treatment option for COVID-19.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (2021)

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Review Biochemistry & Molecular Biology

Natural Polyphenols as Immunomodulators to Rescue Immune Response Homeostasis: Quercetin as a Research Model against Severe COVID-19

Roberta Bernini et al.

Summary: The COVID-19 pandemic caused by SARS-CoV-2 has led to the worst health crisis of this century, with no sufficient evidence to recommend polyphenols as potential immunomodulatory agents against COVID-19.

MOLECULES (2021)

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Article Multidisciplinary Sciences

Merck’s COVID pill loses its lustre: what that means for the pandemic

Max Kozlov

NATURE (2021)

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Article Multidisciplinary Sciences

Nanometer-resolution in situ structure of the SARS-CoV-2 postfusion spike protein

Linhua Tai et al.

Summary: By utilizing cryo-electron tomography, researchers observed prefusion and postfusion spikes in beta-propiolactone-inactivated SARS-CoV-2 virions, and successfully solved the in situ structure of the postfusion spike at nanometer resolution. The study provided detailed information on the fusion core, glycosylation sites, and transmembrane domain location, shedding light on the mechanism of fusion pore formation through spike oligomerization patterns on the viral membrane.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

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Article Multidisciplinary Sciences

Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A

Kris M. White et al.

Summary: The study revealed that plitidepsin possesses potent antiviral activity against SARS-CoV-2, more effective than the approved drug remdesivir. By inhibiting the eukaryotic translation elongation factor 1A, plitidepsin can significantly reduce viral replication of SARS-CoV-2 in the lungs of mice, making it a promising candidate for COVID-19 treatment.

SCIENCE (2021)

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Review Pharmacology & Pharmacy

An overview of ProTide technology and its implications to drug discovery

Michaela Serpi et al.

Summary: The ProTide technology, a phosphate prodrug method, has been successful in delivering new antiviral drugs and shows promise in oncology. Its application to non-nucleoside-based small molecules is emerging and proving effective in various therapeutic areas. Investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies are deemed necessary for the future development of these compounds.

EXPERT OPINION ON DRUG DISCOVERY (2021)

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Editorial Material Pharmacology & Pharmacy

Angiotensin Receptor Blockers for COVID-19: Pathophysiological and Pharmacological Considerations About Ongoing and Future Prospective Clinical Trials

Rodolfo Pedro Rothlin et al.

Summary: The COVID-19 pandemic necessitates a quick response to find therapeutic tools that can effectively reduce morbidity and mortality. Inhibition of the renin-angiotensin system is being explored as a potential pathway to alleviate lung inflammation driven by angiotensin II, leading to the initiation of prospective clinical trials. The interpretation of these trials' results will depend on the stage and severity of the disease, as well as the timing and dosage of the prescribed medications in relation to the diagnosis of COVID-19.

FRONTIERS IN PHARMACOLOGY (2021)

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Review Health Care Sciences & Services

Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review

Sultan A. M. Saghir et al.

Summary: Following the outbreak of the COVID-19 pandemic, chloroquine and hydroxychloroquine were tested for treatment purposes, but clinical trials showed they did not provide any clinical benefits to patients, and therefore are not recommended for use in COVID-19 patients outside of clinical trials.

THERAPEUTICS AND CLINICAL RISK MANAGEMENT (2021)

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Review Pharmacology & Pharmacy

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Andrew Bryant et al.

Summary: The study shows that ivermectin treatment can significantly reduce COVID-19 mortality and potentially prevent disease progression. However, evidence for ivermectin chemoprophylaxis remains low certainty and requires further research.

AMERICAN JOURNAL OF THERAPEUTICS (2021)

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Letter Biochemistry & Molecular Biology

The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable

Jack M. Lawrence et al.

NATURE MEDICINE (2021)

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Review Microbiology

Structural biology of SARS-CoV-2 and implications for therapeutic development

Haitao Yang et al.

Summary: The COVID-19 pandemic caused by SARS-CoV-2 has led to an unprecedented global health crisis, with limited therapeutic options available. Understanding the structure and function of the 29 proteins encoded by SARS-CoV-2 is crucial for developing novel therapeutics and treatment interventions. These proteins play various roles in the viral life cycle, from entry into host cells to genome replication and transcription, highlighting their potential as targets for therapeutic interventions.

NATURE REVIEWS MICROBIOLOGY (2021)

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Editorial Material Biochemistry & Molecular Biology

Molnupiravir: coding for catastrophe

Brandon Malone et al.

Summary: Molnupiravir disrupts the accuracy of SARS-CoV-2 genome replication and prevents viral propagation by fostering error accumulation, a process known as 'error catastrophe'.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2021)

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Review Multidisciplinary Sciences

The efficacy and safety of Favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials

Soheil Hassanipour et al.

Summary: The meta-analysis of Favipiravir in the treatment of COVID-19 showed significant clinical improvement in the Favipiravir group compared to the control group after seven days of hospitalization. However, there was no significant difference in viral clearance and oxygen therapy requirement between the two groups. The mortality rate was approximately 30% lower in the Favipiravir group, but this finding was not statistically significant.

SCIENTIFIC REPORTS (2021)

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Article Microbiology

Current status of therapeutic monoclonal antibodies against SARS-CoV-2

Sanjeev Kumar et al.

PLOS PATHOGENS (2021)

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Article Critical Care Medicine

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER) : a randomised, double-blind, parallel-group, placebo- controlled phase 3 trial

Vincent C. Marconi et al.

Summary: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard care alone, and was associated with reduced mortality in hospitalised adults with COVID-19.

LANCET RESPIRATORY MEDICINE (2021)

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Review Public, Environmental & Occupational Health

Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials

Tejas K. Patel et al.

Summary: The addition of lopinavir-ritonavir to standard care for COVID-19 patients did not show significant benefits in terms of mortality, virological cure, or radiological improvement, but was associated with a higher risk of adverse events compared to supportive care.

JOURNAL OF INFECTION AND PUBLIC HEALTH (2021)

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Review Biochemistry & Molecular Biology

Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza

Yalda Rahbar Saadat et al.

Summary: The COVID-19 pandemic has highlighted the limited therapeutic options for controlling SARS-CoV-2 infections, indicating a need for additional therapeutic targets. The S glycoprotein of the virus can enter host cells through endosomal and non-endosomal pathways, where it is activated by host proteases like furin and TMPRSS2. Targeted inhibition of host proteases may be used as a therapeutic approach for viral infections.

FRONTIERS IN MOLECULAR BIOSCIENCES (2021)

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Article Health Care Sciences & Services

Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19

Michail Papapanou et al.

Summary: Plitidepsin, primarily acting on host cell's eukaryotic translation elongation factor 1α (eEF1A), demonstrates superior ex vivo efficacy in anti-SARS-CoV-2 properties and potential antiviral effect against B.1.1.7 variant. Its well-studied safety profile may accelerate its repurposing chances for COVID-19 treatment. Despite preclinical efficacy, current clinical evidence on plitidepsin is inadequate for registration in COVID-19 patients, warranting multicentre trials for its efficacy.

JOURNAL OF PERSONALIZED MEDICINE (2021)

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Review Biochemistry & Molecular Biology

The JAK/STAT signaling pathway: from bench to clinic

Xiaoyi Hu et al.

Summary: The JAK/STAT signaling pathway is a crucial cellular signal transduction pathway, associated with various cancers and autoimmune diseases. Researchers discussed the composition, activation, and regulation of this pathway, as well as its role in diseases.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2021)

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Article Immunology

Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape

John S. Tregoning et al.

Summary: The development and rollout of vaccines have brought hope for controlling the COVID-19 pandemic, with vaccines proving highly effective in preventing disease. However, challenges remain in ensuring equitable access to vaccines globally, as well as lessons to be learned for controlling pandemics in the future.

NATURE REVIEWS IMMUNOLOGY (2021)

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Article Medicine, General & Internal

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19

Michael A. Puskarich et al.

Summary: The study found that losartan did not reduce hospitalizations in low-risk outpatients with mild symptomatic COVID-19, and viral load was not affected by the treatment. This suggests that initiation of losartan treatment for this group is not supported.

ECLINICALMEDICINE (2021)

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Article Medicine, General & Internal

Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial

Jesper D. Gunst et al.

Summary: This study evaluated the efficacy and safety of the TMPRSS2 inhibitor camostat mesilate in Covid-19 patients through a randomized controlled trial. The results showed that camostat mesilate treatment did not prolong time to clinical improvement and did not increase the occurrence of adverse events.

ECLINICALMEDICINE (2021)

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Review Medicine, General & Internal

Ivermectin for preventing and treating COVID-19

Maria Popp et al.

Summary: The current evidence regarding the efficacy and safety of ivermectin for treating or preventing COVID-19 is very low to low-certainty, with most completed studies being small and of low quality. Ongoing studies may provide more definitive answers. Overall, reliable evidence does not support the use of ivermectin for COVID-19 treatment or prevention without well-designed randomized trials.

COCHRANE DATABASE OF SYSTEMATIC REVIEWS (2021)

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Letter Cell Biology

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Manli Wang et al.

CELL RESEARCH (2020)

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Review Rheumatology

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Eva Schrezenmeier et al.

NATURE REVIEWS RHEUMATOLOGY (2020)

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Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Daniel Wrapp et al.

SCIENCE (2020)

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Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Alexandra C. Walls et al.

CELL (2020)

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Review Chemistry, Medicinal

Drug Development and Medicinal Chemistry Efforts toward SARS-Coronavirus and Covid-19 Therapeutics

Arun K. Ghosh et al.

CHEMMEDCHEM (2020)

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Article Infectious Diseases

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Christian A. Devaux et al.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (2020)

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Three cases of treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen therapy

Sukbin Jang et al.

INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES (2020)

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Editorial Material Cardiac & Cardiovascular Systems

COVID-19 illness in native and immunosuppressed states: A clinical?therapeutic staging proposal

Hasan K. Siddiqi et al.

JOURNAL OF HEART AND LUNG TRANSPLANTATION (2020)

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COVID-19: Drug Targets and Potential Treatments

Carmen Gil et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Biochemical Research Methods

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

Minchen Chien et al.

JOURNAL OF PROTEOME RESEARCH (2020)

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Article Chemistry, Medicinal

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

Robert L. Hoffman et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Giovanni Bolcato et al.

SCIENTIFIC REPORTS (2020)

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FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY (2020)

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Fred Schaper et al.

CYTOKINE & GROWTH FACTOR REVIEWS (2015)

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Heidi A. Neubauer et al.

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Mechanism of Inhibition of Enveloped Virus Membrane Fusion by the Antiviral Drug Arbidol

Elodie Teissier et al.

PLOS ONE (2011)

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