Drug discovery with engineered zinc-finger proteins

@article{Jamieson2003DrugDW,
  title={Drug discovery with engineered zinc-finger proteins},
  author={Andrew C. Jamieson and Jeffrey C. Miller and Carl O. Pabo},
  journal={Nature Reviews Drug Discovery},
  year={2003},
  volume={2},
  pages={361-368}
}
Zinc-finger proteins (ZFPs) that recognize novel DNA sequences are the basis of a powerful technology platform with many uses in drug discovery and therapeutics. These proteins have been used as the DNA-binding domains of novel transcription factors (ZFP TFs), which are useful for validating genes as drug targets and for engineering cell lines for small-molecule screening and protein production. Recently, they have also been used as a basis for novel human therapeutics. Most of our advances in… 
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The studies of endogenous human gene regulation by zinc-finger-based ATFs and other applications are reviewed and Cys(2)His(2)-type ZFPs are introduced.
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The zinc finger design can be used to construct DNA-binding proteins for specific intervention in gene expression, and several applications of such engineered ZFPs are described, including some of therapeutic importance, and also their adaptation for breeding improved crop plants.
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Correlation between functional and binding activities of designer zinc-finger proteins.
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  • 2007
TLDR
The data suggest that the binding affinity of designer zinc-finger proteins with novel specificity might be a determinant for their ability to regulate transcription of a gene of interest.
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The novel functionality obtained by engineered zinc Finger proteins and the computational approaches for prediction of recognition helices of zinc finger proteins that can raise the ability to re-program zinc finger protein with desired novel DNA-binding specificities are explored.
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The zinc finger protein-DNA interaction patterns, challenges in engineering the recognition-specificity of zinc finger proteins, the computational methods of prediction of proteins that recognize specific target DNA sequence and their applications in molecular therapeutics are described.
CELL-FREE SELECTION OF DNA-BINDING PROTEINS FOR FUTURE GENE THERAPY APPLICATIONS ∗
TLDR
A convenient cell-free selection method known as in vitro compartmentalization (IVC) has previously been used to engineer DNA-binding proteins with enzymatic activities, and the method has recently been extended to the engineering of sequence-specific ZFP DNA-binders.
Effects of DNA binding of the zinc finger and linkers for domain fusion on the catalytic activity of sequence-specific chimeric recombinases determined by a facile fluorescent system.
TLDR
The effects of the DNA binding affinity of the zinc finger domains and the linker sequence between ZFPs and recombinase catalytic domains have been assessed and the results provide information relevant to the design of ZFRs that will be useful for sequence-specific genome modification.
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References

SHOWING 1-10 OF 80 REFERENCES
Design of polydactyl zinc-finger proteins for unique addressing within complex genomes.
TLDR
Two six-fingered proteins were created and demonstrated to bind 18 contiguous bp of DNA in a sequence-specific fashion and should be broadly applicable as genome-specific transcriptional switches in gene therapy strategies and the development of novel transgenic plants and animals.
Phage display methods for selecting zinc finger proteins with novel DNA-binding specificities.
TLDR
This chapter describes the methods for (1) preparing zinc finger phage libraries and (2) selecting phage, with new DNA-binding specificities, with desired DNA sequence specificities.
Structure-based design of a dimeric zinc finger protein.
TLDR
This zinc finger-GAL4 fusion may serve as a prototype for designed DNA-binding proteins that could exploit advantages of homo- and heterodimer formation, and the adaptability of the Cys2His2 zinc finger motif, to target virtually any site in the genome.
Design and selection of novel Cys2His2 zinc finger proteins.
TLDR
Although there is no simple, general code for zinc finger-DNA recognition, selection strategies have been developed that allow these proteins to be targeted to almost any desired site on double-stranded DNA.
Chemically Regulated Zinc Finger Transcription Factors*
TLDR
The ability to engineer DNA binding specificities of zinc finger proteins enables the construction of ligand-dependent transcriptional regulators with potential for the regulation of virtually any desired artificial or natural promoter.
A rapid, generally applicable method to engineer zinc fingers illustrated by targeting the HIV-1 promoter
TLDR
A rapid and convenient method that can be used to design zinc finger proteins against a variety of DNA-binding sites and yields proteins that bind sequence-specifically to DNA with Kd values in the nanomolar range is presented.
Getting a handhold on DNA: design of poly-zinc finger proteins with femtomolar dissociation constants.
  • J. Kim, C. Pabo
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1998
TLDR
Using this strategy, and linking peptides selected via phage display, should allow the design of novel DNA-binding proteins-with extraordinary affinity and specificity-for use in biological research and gene therapy.
Improved DNA binding specificity from polyzinc finger peptides by using strings of two-finger units.
  • M. Moore, A. Klug, Y. Choo
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
TLDR
This work shows that by changing the way in which zinc finger arrays are constructed--by linking three two-finger domains rather than two three-finger units--far greater target specificity can be achieved through increased discrimination against mutated or closely related sequences.
In vitro selection of zinc fingers with altered DNA-binding specificity.
TLDR
Random mutagenesis and phage display is used to alter the DNA-binding specificity of Zif268, a transcription factor that contains three zinc finger domains, with the greatest affinity being for the DNA binding site for which they were sorted.
Regulation of endogenous gene expression with a small-molecule dimerizer
TLDR
By directly regulating zinc-finger protein (ZFP) activity, this work could circumvent difficulties encountered in the generation of cell lines stably expressing conventional unregulated activators and result in VEGF protein expression levels several-fold greater than those produced by the natural hypoxic response.
...
1
2
3
4
5
...