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Antimicrobial Agents and Chemotherapy, March 2006, p. 984-993, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.984-993.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

VP35 Knockdown Inhibits Ebola Virus Amplification and Protects against Lethal Infection in Mice

Sven Enterlein,^1, Kelly L. Warfield,^2, Dana L. Swenson,² David A. Stein,³ Jeffery L. Smith,² C. Scott Gamble,² Andrew D. Kroeker,³ Patrick L. Iversen,³ Sina Bavari,^2* and Elke Mühlberger^1*

Department of Virology, Philipps-University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany,¹ U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702-5011,² AVI BioPharma Inc., Corvallis, Oregon³

Received 29 June 2005/ Returned for modification 5 August 2005/ Accepted 3 January 2006

Phosphorodiamidate morpholino oligomers (PMO) are a class of uncharged single-stranded DNA analogs modified such that each subunit includes a phosphorodiamidate linkage and morpholine ring. PMO antisense agents have been reported to effectively interfere with the replication of several positive-strand RNA viruses in cell culture. The filoviruses, Marburg virus and Ebola virus (EBOV), are negative-strand RNA viruses that cause up to 90% lethality in human outbreaks. There is currently no commercially available vaccine or efficacious therapeutic for any filovirus. In this study, PMO conjugated to arginine-rich cell-penetrating peptide (P-PMO) and nonconjugated PMO were assayed for the ability to inhibit EBOV infection in cell culture and in a mouse model of lethal EBOV infection. A 22-mer P-PMO designed to base pair with the translation start site region of EBOV VP35 positive-sense RNA generated sequence-specific and time- and dose-dependent inhibition of EBOV amplification in cell culture. The same oligomer provided complete protection to mice when administered before or after an otherwise lethal infection of EBOV. A corresponding nonconjugated PMO, as well as nonconjugated truncated versions of 16 and 19 base residues, provided length-dependent protection to mice when administered prophylactically. Together, these data suggest that antisense PMO and P-PMO have the potential to control EBOV infection and are promising therapeutic candidates.

Both authors contributed equally to this work.

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