Inhibition of HSV-1 ocular infection with morpholino oligomers targeting ICP0 and ICP27

Moerdyk-Schauwecker, Megan; Stein, David A.; Eide, Kathleen; Blouch, Robert E.; Bildfell, Rob; Iversen, Patrick L.; Jin, Ling

doi:10.1016/j.antiviral.2009.07.020

Cited by 33 publications

(38 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Morpholinos are synthetic molecules that can modify gene expression by blocking translation or splicing, and their efficacy in decreasing protein abundance has been demonstrated in vitro and in vivo (Bottcher-Friebertshauser et al, 2011; Krahling et al, 2009; Moerdyk-Schauwecker et al, 2009; Moulton and Moulton, 2010). The Morpholino we designed binds specifically to an intron-exon junction of ATP2C1 , interferes with its splicing, and therefore reduces its abundance (Figure S6B).…”

Section: Resultsmentioning

confidence: 99%

Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread

Hoffmann

Schneider

Blomen

et al. 2017

Cell Host & Microbe

View full text Add to dashboard Cite

SUMMARY Respiratory and arthropod-borne viral infections are a global threat due to the lack of effective antivirals and vaccines. A potential strategy is to target host proteins required for viruses but non-essential for the host. To identify such proteins, we performed a genome-wide knockout screen in human haploid cells and identified the calcium pump SPCA1. SPCA1 is required by viruses from the Paramyxo-, Flavi-, and Togaviridae families, including measles, dengue, West Nile, Zika, and chikungunya viruses. Calcium transport activity is required for SPCA1 to promote virus spread. SPCA1 regulates proteases within the trans-Golgi network that require calcium for their activity and are critical for virus glycoprotein maturation. Consistent with these findings, viral glycoproteins fail to mature in SPCA1-deficient cells preventing viral spread, which is evident even in cells with partial loss of SPCA1. Thus, SPCA1 is an attractive antiviral host target for a broad spectrum of established and emerging viral infections.

show abstract

Section: Resultsmentioning

confidence: 99%

Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread

Hoffmann

Schneider

Blomen

et al. 2017

Cell Host & Microbe

View full text Add to dashboard Cite

show abstract

“…PMO are often designed against sequences in the 5Ј untranslated region (UTR) and/or the AUG translation start codon region of mRNA, for the purpose of interfering with early events in the process of translation (10,35,39). PMO have also been shown to be capable of interfering with spliceosome-mediated reactions of mRNA maturation (16,24,28,29). To facilitate entry into cells, an arginine-rich cell-penetrating peptide (CPP) may be conjugated to PMO to produce peptide-PMO (PPMO) (25,30,46).…”

mentioning

confidence: 99%

Inhibition of Influenza Virus Infection in Human Airway Cell Cultures by an Antisense Peptide-Conjugated Morpholino Oligomer Targeting the Hemagglutinin-Activating Protease TMPRSS2

Böttcher‐Friebertshäuser

Stein

Klenk

et al. 2011

J Virol

Self Cite

100

View full text Add to dashboard Cite

Influenza A viruses constitute a major and ongoing global public health concern. Current antiviral strategies target viral gene products; however, the emergence of drug-resistant viruses highlights the need for novel antiviral approaches. Cleavage of the influenza virus hemagglutinin (HA) by host cell proteases is crucial for viral infectivity and therefore presents a potential drug target. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded-DNA-like antisense agents that readily enter cells and can act as antisense agents by sterically blocking cRNA. Here, we evaluated the effect of PPMO targeted to regions of the pre-mRNA or mRNA of the HA-cleaving protease TMPRSS2 on proteolytic activation and spread of influenza viruses in human Calu-3 airway epithelial cells. We found that treatment of cells with a PPMO (T-ex5) designed to interfere with TMPRSS2 pre-mRNA splicing resulted in TMPRSS2 mRNA lacking exon 5 and consequently the expression of a truncated and enzymatically inactive form of TMPRSS2. Altered splicing of TMPRSS2 mRNA by the T-ex5 PPMO prevented HA cleavage in different human seasonal and pandemic influenza A viruses and suppressed viral titers by 2 to 3 log 10 units, strongly suggesting that TMPRSS2 is responsible for HA cleavage in Calu-3 airway cells. The data indicate that PPMO provide a useful reagent for investigating HA-activating proteases and may represent a promising strategy for the development of novel therapeutics to address influenza infections.

show abstract

“…Moerdyk-Schauwecker et al tackled the reactivation of another DNA virus, the herpes simplex virus type 1 (HSV-1) [86]. They investigated the antiviral activities of five (RXR) 4 XB-conjugated PMOs directed against three HSV-1 immediate-early genes, ICP0, ICP4 and ICP27 crucial for HSV-1 replication.…”

Section: Delivery Of Antisense Agentsmentioning

confidence: 99%

Cell-Penetrating Peptides for Antiviral Drug Development

Delcroix

Riley

2010

Pharmaceuticals

View full text Add to dashboard Cite

Viral diseases affect hundreds of millions of people worldwide, and the few available drugs to treat these diseases often come with limitations. The key obstacle to the development of new antiviral agents is their delivery into infected cells in vivo. Cell-penetrating peptides (CPPs) are short peptides that can cross the cellular lipid bilayer with the remarkable capability to shuttle conjugated cargoes into cells. CPPs have been successfully utilized to enhance the cellular uptake and intracellular trafficking of antiviral molecules, and thereby increase the inhibitory activity of potential antiviral proteins and oligonucleotide analogues, both in cultured cells and in animal models. This review will address the notable findings of these studies, highlighting some promising results and discussing the challenges CPP technology has to overcome for further clinical applications.

show abstract

Inhibition of HSV-1 ocular infection with morpholino oligomers targeting ICP0 and ICP27

Cited by 33 publications

References 65 publications

Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread

Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread

Inhibition of Influenza Virus Infection in Human Airway Cell Cultures by an Antisense Peptide-Conjugated Morpholino Oligomer Targeting the Hemagglutinin-Activating Protease TMPRSS2

Cell-Penetrating Peptides for Antiviral Drug Development

Contact Info

Product

Resources

About