The global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), named coronavirus disease 2019, has infected more than 8.9 million people worldwide. This calls for urgent effective therapeutic measures. RNAdependent RNA polymerase (RdRp) activity in viral transcription and replication has been recognized as an attractive target to design novel antiviral strategies. Although SARS-CoV-2 shares less genetic similarity with SARS-CoV (~79%) and Middle East respiratory syndrome coronavirus (~50%), the respective RdRps of the three coronaviruses are highly conserved, suggesting that RdRp is a good broad-spectrum antiviral target for coronaviruses. In this review, we discuss the antiviral potential of RdRp inhibitors (mainly nucleoside analogs) with an aim to provide a comprehensive account of drug discovery on SARS-CoV-2.

There is a strong rationale to consider future cell therapeutic approaches for cystic fibrosis (CF) in which autologous proximal airway basal stem cells, corrected for CFTR mutations, are transplanted into the patient's lungs. We assessed the possibility of editing the CFTR locus in these cells using zinc-finger nucleases and have pursued two approaches. The first, mutation-specific correction, is a footprint-free method replacing the CFTR mutation with corrected sequences. We have applied this approach for correction of DF508, demonstrating restoration of mature CFTR protein and function in air-liquid interface cultures established from bulk edited basal cells. The second is targeting integration of a partial CFTR cDNA within an intron of the endogenous CFTR gene, providing correction for all CFTR mutations downstream of the integration and exploiting the native CFTR promoter and chromatin architecture for physiologically relevant expression. Without selection, we observed highly efficient, site-specific targeted integration in basal cells carrying various CFTR mutations and demonstrated restored CFTR function at therapeutically relevant levels. Significantly, Omni-ATAC-seq analysis revealed minimal impact on the positions of open chromatin within the native CFTR locus. These results demonstrate efficient functional correction of CFTR and provide a platform for further ex vivo and in vivo editing.

The 21st century has witnessed three outbreaks of coronavirus (CoVs) infections caused by severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, spreads rapidly and since the discovery of the first COVID-19 infection in December 2019, has caused 1.2 million deaths worldwide and 226,777 deaths in the United States alone. The high amino acid similarity between SARS-CoV and SARS-CoV-2 viral proteins supports testing therapeutic molecules that were designed to treat SARS infections during the 2003 epidemic. In this review, we provide information on possible COVID-19 treatment strategies that act via inhibition of the two essential proteins of the virus, 3C-like protease (3CL pro ) or papain-like protease (PL pro ). K E Y W O R D S 3 chymotrypsin-like cysteine protease, coronavirus main protease, COVID-19, papain-like cysteine protease, SARS coronavirus, SARS-CoV-2 1 | INTRODUCTION Coronaviruses (CoVs) belong to the Nidovirales order of enveloped positive-sense single-stranded RNA viruses. Before 2002, there were only two known human CoV species, HCoV-229E and HCoV-OC43, with infections exhibiting symptoms similar to those of the common cold caused by rhinovirus. These two CoV were identified in 1965 and have been extensively studied for the following 20 years. 1 There are now seven known species of human CoVs (HCoVs): HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV, and SARS-CoV-2 belonging to alpha-and beta-coronaviruses (Figure 1A). 2 About 30% of mild upper respiratory diseases are caused by HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. 3,4 SARS-CoV and MERS-CoV, which first appeared in China in 2002 and in Saudi Arabia in 2012, respectively, caused severe health and economic crisis at the global level. Even though its infection rate is slow, MERS-CoV infections are still ongoing and between January 2020 and September 2020, 61 new cases were reported with 21 deaths. The mortality rate of MERS ( 30%) is about three times more than that of SARS (10%).The recently emerged novel SARS-CoV-2, which is currently wreaking havoc worldwide, has infected 44 million individuals and caused 1.2 million deaths as of November 10, 2020 (https:// coronavirus.jhu.edu/map.html). SARS-CoV-2 infection results in coronavirus disease 2019 and the clinical manifestations include fever (88.7%), dry cough (67.8%), sore throat (13.9%), dyspnea (18.6%), fatigue (38.1%) and gastrointestinal symptoms (8.8%). SARS-CoV-2 is a close cousin of SARS-CoV, sharing an overall amino-acid sequence identity of 82%. 5 Based on this similarity it is reasonable to assume that knowledge of the molecular pathogenesis of SARS-CoV could help develop SARS-CoV-2 treatment strategies. Currently, the US FDA has approved remdesivir

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Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.