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Antimicrobial Agents and Chemotherapy, March 2003, p. 1052-1061, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1052-1061.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Structure-Based Design and Engineering of a Nontoxic Recombinant Pokeweed Antiviral Protein with Potent Anti-Human Immunodeficiency Virus Activity

Fatih M. Uckun,1,2* Francis Rajamohan,1,3 Sharon Pendergrass,2 Zahide Ozer,3 Barbara Waurzyniak,1,4 and Chen Mao3

Biotherapy Program, Parker Hughes Cancer Center,1 Departments of Protein Engineering,3 Virology, Parker Hughes Institute, and,2 Paradigm Pharmaceuticals, St. Paul, Minnesota4

Received 7 May 2002/ Returned for modification 8 August 2002/ Accepted 3 December 2002

A molecular model of pokeweed antiviral protein (PAP)-RNA interactions was used to rationally engineer FLP-102(151AA152) and FLP-105(191AA192) as nontoxic PAPs with potent anti-human immunodeficiency virus (anti-HIV) activities. FLP-102 and FLP-105 have been produced in Escherichia coli and tested both in vitro and in vivo. These proteins depurinate HIV type 1 (HIV-1) RNA much better than rRNA and are more potent anti-HIV agents than native PAP or recombinant wild-type PAP. They are substantially less toxic than native PAP in BALB/c mice and exhibit potent in vivo activities against genotypically and phenotypically nucleoside reverse transcriptase inhibitor-resistant HIV-1 in a surrogate human peripheral blood lymphocyte (Hu-PBL) SCID mouse model of human AIDS. Rationally engineered nontoxic recombinant PAPs such as FLP-102 and FLP-105 may provide the basis for effective salvage therapies for patients harboring highly drug-resistant strains of HIV-1. The documented in vitro potencies of FLP-102 and FLP-105, their in vivo antiretroviral activities in the HIV-infected Hu-PBL SCID mouse model, and their favorable toxicity profiles in BALB/c mice warrant the further development of these promising new biotherapeutic agents.

* Corresponding author. Mailing address: Parker Hughes Cancer Center, 2699 Patton Rd., St. Paul, MN 55113. Phone: (651) 796-5450. Fax: (651) 796-5493. E-mail: fatih_uckun{at}ih.org.

Antimicrobial Agents and Chemotherapy, March 2003, p. 1052-1061, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1052-1061.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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