4.7 Review

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

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Crystal structure of SARS-CoV-2 papain-like protease

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Summary: This study provided structural frameworks for PLpro inhibitor design targeting SARS-CoV-2, showing that existing SARS-CoV PLpro inhibitors have some efficacy against SARS-CoV-2 and explored the inhibition mechanism of GRL0617.

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Cryo-EM Structure of an Extended SARS-CoV-2 Replication and Transcription Complex Reveals an Intermediate State in Cap Synthesis

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Summary: The study presents a structural snapshot of SARS-CoV-2 RTC during mRNA transcription, revealing the interaction between nsp9 and nsp12, as well as the catalytic activity of nsp12 NiRAN. The results demonstrate an intermediate state of RTC towards mRNA synthesis, providing valuable information for antiviral drug development.
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Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection

Hangping Yao et al.

Summary: This study developed a therapeutic antibody cocktail against SARS-CoV-2 by exploiting antibody cooperativity, consisting of two antibodies that achieved synergistic neutralization through S1 shielding and conformational locking, blocking receptor attachment and viral membrane fusion to combat viral mutation escape. Additionally, a hypothetical third antibody partner was identified for further reinforcement as pan-SARS-CoVs therapeutics.

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A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**

Kai S. Yang et al.

Summary: This study developed a series of SARS-CoV-2 main protease inhibitors with high potency by forming reversible covalent bonds with the active site cysteine C145, showing potential as COVID-19 treatment options. The most potent compound, MPI3, demonstrated a Ki value of 8.3 nM. Inhibitor MPI5 and MPI8 completely prevented SARS-CoV-2-induced cytopathogenic effect in cells at low concentrations, surpassing some existing molecules under clinical investigation for COVID-19 treatment. Further exploration of chemical space is needed to develop SC2M(Pro) inhibitors with ultra-high antiviral potency.

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Article Multidisciplinary Sciences

Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

Thomas G. Flower et al.

Summary: The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-angstrom resolution by X-ray crystallography, revealing unique dimerization interfaces that may allow the protein to form large-scale assemblies, potentially mediating immune suppression and evasion activities.

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

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The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery

Ziyang Fu et al.

Summary: SARS-CoV-2 PLpro enzyme plays a critical role in virus maturation, host inflammation regulation, and antiviral immune responses, making it a promising drug target. The inhibitor GRL0617 has shown to effectively inhibit PLpro and has promising antiviral activity in vitro. This study provides insights into the mechanism of action of GRL0617 and highlights the potential of targeting the PLpro enzyme for antiviral drug discovery.

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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.

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A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CLpro Inhibitor PF-00835231 as a Potential New Treatment for COVID-19

Maren de Vries et al.

Summary: The study compares the efficacy of the potential antiviral drug PF-00835231 with other inhibitors on SARS-CoV-2 in vitro, showing that PF-00835231 has similar or higher potency. It targets the main protease of the virus, potentially providing a new treatment option for COVID-19.

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Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Dami A. Collier et al.

Summary: The B.1.1.7 variant of SARS-CoV-2 exhibited reduced neutralization by vaccines and antibodies from recovered COVID-19 patients, with a more substantial loss seen when introducing the E484K mutation. This mutation poses a threat to the efficacy of the BNT162b2 vaccine.

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Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin

Wanchao Yin et al.

Summary: Suramin, an old drug, serves as a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase by blocking RNA binding. It is at least 20 times more effective than the approved nucleotide drug for COVID-19 treatment, remdesivir. The cryo-electron microscopy structure of the viral RdRp complexed with suramin reveals its mechanism of action in inhibiting viral replication.

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SARS-CoV-2 M-pro inhibitors with antiviral activity in a transgenic mouse model

Jingxin Qiao et al.

Summary: The study designed and synthesized 32 new M-pro inhibitors containing bicycloproline, which showed inhibitory effects on SARS-CoV-2. Compounds MI-09 and MI-30 exhibited excellent antiviral activity in cell-based assays and significantly reduced lung viral loads and lung lesions in a transgenic mouse model of SARS-CoV-2 infection. Both also displayed good pharmacokinetic properties and safety in rats.

SCIENCE (2021)

Article Multidisciplinary Sciences

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

Kevin R. McCarthy et al.

Summary: The translation above discusses zoonotic pandemics caused by animal viruses spilling over into highly susceptible human populations, specifically focusing on the evolution of coronaviruses in human hosts and the impact of recurrent deletions in the spike glycoprotein on antibody epitopes. These studies help understand the antigenic evolution and adaptive evolution of SARS-CoV-2.

SCIENCE (2021)

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A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Shin-ichiro Hattori et al.

Summary: In this study, two small-molecule compounds, GRL-1720 and 5h, are characterized for their anti-SARS-CoV-2 properties targeting the virus main protease (M-pro). These compounds showed synergistic antiviral effects when combined with remdesivir in vitro, indicating their potential as lead inhibitors for the development of therapeutics against SARS-CoV-2 infection.

NATURE COMMUNICATIONS (2021)

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Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors

Jerzy Osipiuk et al.

Summary: The study focused on papain-like protease (PLpro) as a potential target for antivirals against SARS-CoV-2, identifying inhibitors and their interactions with the enzyme. The findings demonstrate the potential for developing high-affinity inhibitors through structure-based drug design efforts targeting PLpro.

NATURE COMMUNICATIONS (2021)

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Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14+ monocytes

Ziliang Zhou et al.

Summary: SARS-CoV-2 ORF7a interacts efficiently with human CD14(+) monocytes, triggering inflammatory responses such as decreased HLA expression and increased production of proinflammatory cytokines. This suggests that ORF7a may be a key immunomodulating factor in the severe immune response seen in COVID-19 patients.

ISCIENCE (2021)

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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Matthew McCallum et al.

Summary: The study identifies 41 human monoclonal antibodies that recognize the N-terminal domain of the SARS-CoV-2 spike protein and exhibit strong neutralizing activity. These antibodies inhibit cell-to-cell fusion, activate effector functions, and protect animals from virus challenge, highlighting the importance of NTD-specific neutralizing antibodies for protective immunity and vaccine development. Several SARS-CoV-2 variants with mutations in the NTD supersite suggest ongoing selective pressure on the virus.
Article Biochemistry & Molecular Biology

The SARS-unique domain (SUD) of SARS-CoV and SARS-CoV-2 interacts with human Paip1 to enhance viral RNA translation

Jian Lei et al.

Summary: Research confirmed the interaction between the SUD domain of SARS-CoV and SARS-CoV-2 with human PABP-interacting protein 1 (Paip1), proposing a possible mechanism for stimulating viral translation.

EMBO JOURNAL (2021)

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Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex

Brandon Malone et al.

Summary: Backtracking, a common regulatory feature in transcription, is found in viruses as well, with evidence suggesting that SARS-CoV-2 RdRp may utilize backtracking for viral transcription and replication. The interaction between RdRp and nsp13 helicase facilitates backtracking, which may aid in proofreading and antiviral resistance for SARS-CoV-2.

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

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X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Sebastian Guenther et al.

Summary: The study identified 37 compounds that bind to the SARS-CoV-2 main protease through a high-throughput x-ray crystallographic screen of two repurposing drug libraries. Among these compounds, one peptidomimetic and six nonpeptidic compounds showed antiviral activity in cell-based viral reduction assays at nontoxic concentrations. The identification of two allosteric binding sites presents potential targets for drug development against SARS-CoV-2.

SCIENCE (2021)

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Cross-reactive serum and memory B-cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Ge Song et al.

Summary: This study examines the impact of pre-existing immunity to seasonal endemic coronaviruses on antibody responses to SARS-CoV-2, finding weak evidence of pre-existing cross-reactive serum antibodies in pre-pandemic donors, but evidence of pre-existing cross-reactive memory B cells activated during SARS-CoV-2 infection. Monoclonal antibodies show varying degrees of cross-reactivity with betacoronaviruses, and one neutralizing antibody specific to the S2 subunit of the S protein is identified, suggesting that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

NATURE COMMUNICATIONS (2021)

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A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes

Yu Guo et al.

Summary: This study identified potent antibodies from COVID-19 convalescent patients that can bind to SARS-CoV-2 Spike protein, with further engineered modifications to enhance their effectiveness and safety. The engineered antibody showed promising results in clearing the virus in a rhesus monkey model of COVID-19, suggesting its potential as a treatment option against SARS-CoV-2 related diseases.

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Article Biochemistry & Molecular Biology

Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes

Dan Fu et al.

Summary: This study utilized advanced technology to immunize and isolate 25 human neutralizing antibodies with potent neutralizing activities, one of which was named PR1077 and showed antiviral effects. The research also revealed novel epitopes on the receptor-binding motif for these antibodies, providing new directions for the development of monoclonal antibody therapy for COVID-19.

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High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

Yao Zhao et al.

Summary: This study identified four compounds that inhibit SARS-CoV-2 PLpro with strong antiviral activities, particularly highlighting YM155's unique binding mode targeted at three hot spots on PLpro, suggesting their potential as clinical leads for COVID-19 treatments.

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SARS-CoV-2 variants, spike mutations and immune escape

William T. Harvey et al.

Summary: The evolution of SARS-CoV-2 has been characterized by the emergence of mutations and variants that impact virus characteristics. Manufacturers are preparing for possible updates to vaccines in response to changes in the virus population, and it is crucial to monitor genetic and antigenic changes alongside experiments to understand the impacts of mutations.

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Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs

David M. Kern et al.

Summary: The cryo-EM structure of SARS-CoV-2 ORF3a reveals a new fold conserved in coronaviruses, with functional experiments showing ion channel activity that could be crucial for viral infectivity. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, indicating it could be a potential target for vaccines or therapeutics. The study also identifies structural features of 3a and potential inhibitors that could be used in treating COVID-19 and other coronavirus diseases.

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The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase

Yousef M. O. Alhammad et al.

Summary: The Mac1 proteins in SARS-CoV-2 and other CoVs are MAR-hydrolases with similar functions, suggesting compounds targeting these proteins may have broad anti-CoV activity. Understanding the biochemistry and enzyme activity of these proteins is critical for developing novel therapeutic strategies against COVID-19.

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