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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,{dagger} Kelly L. Warfield,2,{dagger} 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 Mühlberger1*

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.

* Corresponding author. Mailing address for Elke Mühlberger: Department of Virology, Philipps-University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany. Phone: 49 6421 28-65357. Fax: 49 6421 28-68962. E-mail: muehlber{at}staff.uni-marburg.de. Mailing address for Sina Bavari: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011. Phone: (301) 619-4246. Fax: (301) 619-2348. E-mail: sina.bavari{at}us.army.mil.

{dagger} Both authors contributed equally to this work.

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.



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