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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Commun 2021 ; 12 (1): 4270 Nephropedia Template TP
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Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance #MMPMID34257311
Fareh M; Zhao W; Hu W; Casan JML; Kumar A; Symons J; Zerbato JM; Fong D; Voskoboinik I; Ekert PG; Rudraraju R; Purcell DFJ; Lewin SR; Trapani JA
Nat Commun 2021[Jul]; 12 (1): 4270 PMID34257311show ga
The recent dramatic appearance of variants of concern of SARS-coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape from host immunity and antiviral therapeutics. Here, we employ genome-wide computational prediction and single-nucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved >98% silencing efficiency in virus-free models. Further, optimized and multiplexed Cas13b CRISPR RNAs (crRNAs) suppress viral replication in mammalian cells infected with replication-competent SARS-CoV-2, including the recently emerging dominant variant of concern B.1.1.7. The comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches does not impair the capacity of a potent single crRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 strains in infected mammalian cells, including the Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint for antiviral drug development to suppress and prevent a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.
|*Mutation[MESH]
|Animals[MESH]
|Antiviral Agents/pharmacology[MESH]
|COVID-19 Drug Treatment[MESH]
|COVID-19/virology[MESH]
|CRISPR-Cas Systems[MESH]
|Chlorocebus aethiops[MESH]
|Clustered Regularly Interspaced Short Palindromic Repeats[MESH]