Uckun Fatih M, Rajamohan Francis, Pendergrass Sharon, Ozer Zahide, Waurzyniak Barbara, Mao Chen
Biotherapy Program, Parker Hughes Cancer Center, St. Paul, Minnesota 55113, USA.
Antimicrob Agents Chemother. 2003 Mar;47(3):1052-61. doi: 10.1128/AAC.47.3.1052-1061.2003.
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.
利用商陆抗病毒蛋白（PAP）与RNA相互作用的分子模型，合理设计了FLP - 102（(151)AA(152)）和FLP - 105（(191)AA(192)），使其成为具有高效抗人类免疫缺陷病毒（抗HIV）活性的无毒PAP。FLP - 102和FLP - 105已在大肠杆菌中产生，并进行了体外和体内测试。这些蛋白质对1型人类免疫缺陷病毒（HIV - 1）RNA的脱嘌呤作用比rRNA好得多，并且比天然PAP或重组野生型PAP更有效地抗HIV。在BALB/c小鼠中，它们的毒性比天然PAP低得多，并且在人类艾滋病的替代人类外周血淋巴细胞（Hu - PBL）SCID小鼠模型中，对基因型和表型耐核苷类逆转录酶抑制剂的HIV - 1表现出强大的体内活性。合理设计的无毒重组PAP，如FLP - 102和FLP - 105，可能为携带高度耐药HIV - 1毒株的患者提供有效的挽救治疗基础。FLP - 102和FLP - 105已记录的体外效力、它们在HIV感染的Hu - PBL SCID小鼠模型中的体内抗逆转录病毒活性以及它们在BALB/c小鼠中良好的毒性特征，保证了这些有前景的新型生物治疗药物的进一步开发。
