Fourth Generation Inhibitors

Fourth-generation inhibitors are analogous to the small-molecule carcerands first studied by Warmuth and Yoon (53). These self-assembling and programmable macromolecular hemi carcerands (54) would be capable of sensing their environment and disgorging or uncoating an encapsulated or hidden entity at a desired cellular or intracellular location. A representative design is given in Fig. 8. The value of using an ordered protein array in a design of this type is the availability of DNA-binding proteins that bind to DNA or release only in the presence of a small-molecule ligand. Many proteins of this type are known, and it will be possible to engineer responses to desired ligands that will cause the hemi carcerand to disassemble in the presence of high local concentrations of the ligand. Disassembly could be used to release a macromolecule or expose the internal surface of the structure so as to attack or modify certain cellular systems localized in the region of high ligand concentration.

Fig. 7. Bionanotechnological machine for inhibition of human DNA methyl-transferase: a guided Y-Junction. This machine comprises a Y-Junction protein array scaffold that can act as a recombination intermediate so as to activate further the already activated methyltransferase targeting sites (hDnmt1 recognition sequence). The device also has the potential to attract helicases (helicase recognition region). The arms of the Y-Junction carrying the human recognition sequences are each 30 bp long. Thus, they each present an adequate kinetic footprint for the hDnmt1 at each of the dual trapping regions of the inhibitor. The entire system is stabilized by the presence of a trapped bacterial methyltransferase (M^coRII) carrying an NLS that is designed to link the machine to the cellular nuclear transport system so as to place it effectively in the cell nucleus where the bulk of hDnmt1 acts.

Fig. 7. Bionanotechnological machine for inhibition of human DNA methyl-transferase: a guided Y-Junction. This machine comprises a Y-Junction protein array scaffold that can act as a recombination intermediate so as to activate further the already activated methyltransferase targeting sites (hDnmt1 recognition sequence). The device also has the potential to attract helicases (helicase recognition region). The arms of the Y-Junction carrying the human recognition sequences are each 30 bp long. Thus, they each present an adequate kinetic footprint for the hDnmt1 at each of the dual trapping regions of the inhibitor. The entire system is stabilized by the presence of a trapped bacterial methyltransferase (M^coRII) carrying an NLS that is designed to link the machine to the cellular nuclear transport system so as to place it effectively in the cell nucleus where the bulk of hDnmt1 acts.

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