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Antimicrobial Agents and Chemotherapy, May 2009, p. 2089-2099, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00936-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection{triangledown}

Dana L. Swenson ,1,{dagger},{ddagger} Kelly L. Warfield,1,{dagger} Travis K. Warren,1 Candace Lovejoy,2 Jed N. Hassinger,2 Gordon Ruthel,1 Robert E. Blouch,2 Hong M. Moulton,2 Dwight D. Weller,2 Patrick L. Iversen,2* and Sina Bavari1*

U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland,1 AVI BioPharma, Inc., Corvallis, Oregon2

Received 15 July 2008/ Returned for modification 13 September 2008/ Accepted 30 January 2009

Phosphorodiamidate morpholino oligomers (PMOs) are uncharged nucleic acid-like molecules designed to inactivate the expression of specific genes via the antisense-based steric hindrance of mRNA translation. PMOs have been successful at knocking out viral gene expression and replication in the case of acute viral infections in animal models and have been well tolerated in human clinical trials. We propose that antisense PMOs represent a promising class of therapeutic agents that may be useful for combating filoviral infections. We have previously shown that mice treated with a PMO whose sequence is complementary to a region spanning the start codon of VP24 mRNA were protected against lethal Ebola virus challenge. In the present study, we report on the abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection. Additionally, structure-activity relationship evaluations were conducted to assess the enhancement of antiviral efficacy associated with PMO chemical modifications that included conjugation with peptides of various lengths and compositions, positioning of conjugated peptides to either the 5' or the 3' terminus, and the conferring of charge modifications by the addition of piperazine moieties. Conjugation with arginine-rich peptides greatly enhanced the antiviral efficacy of VP24-specific PMOs in infected cells and mice during lethal Ebola virus challenge.

* Corresponding author. Mailing address for Sina Bavari: U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702. Phone: (301) 619-4246. Fax: (301) 619-2348. E-mail: sina.bavari{at}amedd.army.mil. Mailing address for Patrick L. Iversen: AVI BioPharma, Inc., 4575 SW Research Way, Suite 200, Corvallis, OR 97333. Phone: (541) 753-3635. Fax: (541) 754-3545. E-mail: piversen{at}avibio.com

{triangledown} Published ahead of print on 17 February 2009.

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Integrated BioTherapeutics Inc., 20358 Seneca Meadows Parkway, Germantown, MD 20876.

Antimicrobial Agents and Chemotherapy, May 2009, p. 2089-2099, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00936-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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