Structure-based design and engineering of a nontoxic recombinant pokeweed antiviral protein with potent anti-human immunodeficiency virus activity.
A molecular model of pokeweed antiviral protein (PAP)-RNA interactions was used to rationally engineer FLP-102((151)AA(152)) and FLP-105((191)AA(192)) 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.
Uckun
Fatih M
FM
Biotherapy Program, Parker Hughes Cancer Center, St. Paul, Minnesota 55113, USA. faith_uckun@ih.org
Rajamohan
Francis
F
Pendergrass
Sharon
S
Ozer
Zahide
Z
Waurzyniak
Barbara
B
Mao
Chen
C
D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000737:chemistry* / Q000494:pharmacology*; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D015202:Protein Engineering; D011687:Purines / Q000378:metabolism; D012367:RNA, Viral / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D010948:Viral Plaque Assay
D000814:Aniline Compounds; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D010940:Plant Proteins; D011687:Purines; D012367:RNA, Viral; D011994:Recombinant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein; C023650:aniline; C030985:purine