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1.
Nat Commun ; 13(1): 2766, 2022 05 19.
Article in English | MEDLINE | ID: covidwho-1927082

ABSTRACT

A major challenge in coronavirus vaccination and treatment is to counteract rapid viral evolution and mutations. Here we demonstrate that CRISPR-Cas13d offers a broad-spectrum antiviral (BSA) to inhibit many SARS-CoV-2 variants and diverse human coronavirus strains with >99% reduction of the viral titer. We show that Cas13d-mediated coronavirus inhibition is dependent on the crRNA cellular spatial colocalization with Cas13d and target viral RNA. Cas13d can significantly enhance the therapeutic effects of diverse small molecule drugs against coronaviruses for prophylaxis or treatment purposes, and the best combination reduced viral titer by over four orders of magnitude. Using lipid nanoparticle-mediated RNA delivery, we demonstrate that the Cas13d system can effectively treat infection from multiple variants of coronavirus, including Omicron SARS-CoV-2, in human primary airway epithelium air-liquid interface (ALI) cultures. Our study establishes CRISPR-Cas13 as a BSA which is highly complementary to existing vaccination and antiviral treatment strategies.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/pharmacology , Humans , Liposomes , Nanoparticles , SARS-CoV-2/genetics
2.
Cell ; 181(4): 865-876.e12, 2020 05 14.
Article in English | MEDLINE | ID: covidwho-684968

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has highlighted the need for antiviral approaches that can target emerging viruses with no effective vaccines or pharmaceuticals. Here, we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN (prophylactic antiviral CRISPR in human cells), for viral inhibition that can effectively degrade RNA from SARS-CoV-2 sequences and live influenza A virus (IAV) in human lung epithelial cells. We designed and screened CRISPR RNAs (crRNAs) targeting conserved viral regions and identified functional crRNAs targeting SARS-CoV-2. This approach effectively reduced H1N1 IAV load in respiratory epithelial cells. Our bioinformatic analysis showed that a group of only six crRNAs can target more than 90% of all coronaviruses. With the development of a safe and effective system for respiratory tract delivery, PAC-MAN has the potential to become an important pan-coronavirus inhibition strategy.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , CRISPR-Cas Systems , Influenza A Virus, H1N1 Subtype/drug effects , RNA, Viral/antagonists & inhibitors , A549 Cells , Antibiotic Prophylaxis/methods , Base Sequence , Betacoronavirus/genetics , Betacoronavirus/growth & development , COVID-19 , Clustered Regularly Interspaced Short Palindromic Repeats , Computer Simulation , Conserved Sequence , Coronavirus/drug effects , Coronavirus/genetics , Coronavirus/growth & development , Coronavirus Infections/drug therapy , Coronavirus Nucleocapsid Proteins , Coronavirus RNA-Dependent RNA Polymerase , Epithelial Cells/virology , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/growth & development , Lung/pathology , Lung/virology , Nucleocapsid Proteins/genetics , Pandemics , Phosphoproteins , Phylogeny , Pneumonia, Viral/drug therapy , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2 , Viral Nonstructural Proteins/genetics
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