Pokeweed antiviral protein

Irvin, J.D. (1983) Pokeweed antiviral protein. Pharmacol. Ther. 21, 371-387. 

Lambert, J.M., Senter, P.D., Yau-Young, A., Blattler, W.A., and Goldmacher, V.S. (1985) Purified immuno-toxins that are reactive with human lymphoid cells Monoclonal antibodies conjugated to the ribosomeinactivating proteins gelonin and the pokeweed antiviral proteins./. Biol. Chem. 260, 12035-12041. 

Fig. 3.3 shows the principle behind the design of immunotoxins. A number of protein toxins of bacterial and plant origin are useful for the production of immunotoxins. These include the diphtheria toxin and pseudomonas exotoxin from bacteria, and ricin, arbin, pokeweed antiviral proteins, saporin, and gelonin from plants (Pastan et al, 1986 Pastan and FitzGerald, 1991). All of these toxins kill cells by entering the cells, and enzymatically inactivating the translational machinery of the cells. Some, such as diphtheria toxin, arbin, and ricin, are composed of two protein chains, A and B. The B chains bind to the cell-surface... 

Plant RlPs have been classified into three general types based on structure. Type 1 RlPs are monomeric V-glycosidase enzymes of approximately 30 kDa molecular weight and a basic isoelectric point they share a common secondary stmcture around the rRNA-binding cleft, as well as several specific active-site residues (Barbieri et al., 1993). Type 1 RlPs are frequently found in higher plants, but also have been isolated from at least one mushroom (Yao et al., 1998). The best-studied type 1 RlPs are pokeweed antiviral protein, saporin, and barley translation inhibitor (Nielsen and Boston, 2001). Type 1 RlPs are generally considered nontoxic because they lack an effective cell-binding or internalization apparatus. 

The ribosome conformations required for optimal RTA binding and catalysis are stiU under study (Endo et al., 1991 Macbeth and Wool, 1999 Chan et al., 2004 Mansouri et al., 2006). In addition to the rRNA, RTA may interact with specific protein components of the ribosome. Rat ribosomal proteins L9 and PO, both located in the acidic stalk of the ribosome, can be chemically cross-linked with RTA (Vater et al., 1995). Likewise, yeast ribosomal protein L3 interacts with pokeweed antiviral protein, and the binding is dependent on the presence of two specific amino acid residues that are highly conserved among eukaryotes (Hudak et al., 1999). 

Hudak, K.A., Dinman, J.D. and Turner, N.E. (1999) Pokeweed antiviral protein accesses ribosomes by binding to L3. J Biol Chem, 274, 3859-3864. 

Mansouri, S., NouroUahzadeh, E. and Hudak, K.A. (2006) Pokeweed antiviral protein depurinates the sarcin/ricin loop of the rRNA prior to binding of aminoacyl-tRNA to the ribosomal A-site. RNA, 12, 1683-1692. 

Irvin, J. D. and Uckun, F. M. (1997) Pokeweed antiviral protein Ribosome inactivation and therapeutic applications. Pharmacol. Ther. 55, 279-302. 

Myers, D. E., Irvin, J. D., Smith, R. S., Kuebelbeck, V. M., and Uckun, F. M. (1991) Production of a pokeweed antiviral protein (PAP)-containing immunotoxin, B43-PAP, directed against the CD19 human B lineage lymphoid differentiation antigen in highly purified form for human clinical trials. J. Immunol. Methods 136, 221-237. 

Myers, D., Yanishevski, Y., Masson, E., Irvin, J., Evans, W., and Uckun, F. (1995) Favorable pharmacodynamic features and superior anti-leukemic activity of B43 (anti-CD19) immunotoxins containing two pokeweed antiviral protein molecules covalently linked to each monoclonal antibody molecule. Leuk. Lymphoma 18, 93-102. 

Mice Cytomegalovirus Murine Sarcoma Virus Measles Virus Newcastle Disease Virus Pokeweed Antiviral Proteins Pseudorabies Virus Ribosome-Inactivating Proteins Respiratory Syncytial Virus Reverse Transcriptase Sindbis Virus Tobacco Mosaic Virus Vesicular Stomatitis Virus Vaccinia Virus Varicella Zoster Virus... 

Hur, Y. Han, C-T. Maeng, J. Expression Characteristics of Pokeweed Antiviral Proteins (PAPs) Two Distinct Types of Proteins. J. Plant Biol. 1997, 40, 53-60. 

Watanabe, K. Kawasaki, T. Sako, N. Funatsu, G. Actions of Pokeweed Antiviral Protein on Virus-Infected Protoplasts. Japan. Biosci., Biotech., Biochem. 1997, 61, 994-997. 

Pokeweed contains compounds known as pokeweed antiviral proteins, ribosome-inactivating proteins that are currently under investigation in human and animal studies for use in the treatment of HIV and in several cancers, notably leukemia, lymphoma, and Hodgkin s disease (Ek et al. 1998 Hertler and Frankel 1989 Irvin and Uckun 1992 Messinger et al. 1999 Uckun et al. 1999 Waurzyniak et al. 1997). 

No adverse effects on reproductive ability, neonatal survival, or pup development were observed in mice that had been treated prior to pregnancy with an intravaginally administered gel formulation of pokeweed antiviral protein (PAP) at doses of 0,0.025,0.05, or 0.1% PAP, 5 days per week for 13 weeks (D Cruz et al. 2004). No other information on the safety of poke during pregnancy was identified. 

D Cruz, O.J., B. Waurzyniak, and F.M. Uckun. 2004. A 13-week subchronic intravaginal toxicity study of pokeweed antiviral protein in mice. Phytomedicine 11(4) 342-351. 

Waurzyniak, B., E.A. Schneider, N. Turner, et al. 1997. In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin. Clin. Cancer Res. 3(6) 881-890. 

Kurinov, I.V., Myers, D.E., Irvin, J.D., et al., 1999. X-ray crystallographic analysis of the structural basis for the interactions of pokeweed antiviral protein with its active site inhibitor and ribosomal RNA substrate analogs. Protein Sci. 8,1765-1772. 

Rajamohan, E, Engstrom, C.R., Denton, T.J., et al., 1999. High-level expression and purification of biologically active recombinant pokeweed antiviral protein. Protein Expr. Purif. 16, 359-368. 

Rajamohan, R, Mao, C., Uckun, EM., 2001. Binding interactions between the active center cleft of recombinant pokeweed antiviral protein and the alpha-sarcin/ricin stem loop of ribosomal RNA. J. Biol. Chem. 276, 24075-24081. 

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