One of the biggest challenges in medical drug development is the synthesis of drugs that can diffuse across the cell membrane. This requires that the drug be sufficiently nonpolar while at the same time it must be sufficiently polar to have reasonable aqueous solubility, allowing blood transport. One way around this problem is to develop a water soluble drug and a protein "receptor" which would allow drug passage across the membrane. A novel mechanism not based on facilitated diffusion has been developed that allows certain protein sequences to transduce the drug across the membrane (a process called protein transduction or molecular transportation). Researchers have looked to nature to find proteins which can move across the membrane and adapted them for this process. Several viral proteins (including TAT from the HIV virus) possess such properties, which require the presence of a short "transporter" amino acid sequence in the protein. Drugs are covalently attached to the sequence, and carried through the membrane by the short protein sequence. This mechanism does not fit the criteria of facilitated diffusion since the required protein fragment is not a classical receptor. It is amphiphilic and can pass through the membrane even if synthesized in the lab using D-amino acids or if the sequence is scrambled. The fusion domain of the TAT protein is ionic (containing 5-15 Arg residues) and probably interacts initially with negatively charged glycosoaminoglycans on the cell surface. Many different types of drugs can be delivered in this fashion (large to small, proteins, nucleic acids, and large liposomes, etc). The company Cyclacel is developing a proprietary drug system using another protein transducer, Penetratin, a fragment of the antennapedia protein from Drosophila.
Another approach is to design artificial receptors. For example, a ligand that might ordinarily bind to a protein could be covalently modified with a hydrophobic group (often a cholesterol derivative) which would allow it to partition into the cell membrane, exposing the ligand on the cell surface. The surface ligand can then bind its target protein. If the protein is multivalent (can bind more than one ligand per protein, such as an antibody), lateral diffusion and clustering of protein-artificial receptor complexes in the membrane can occur, as well as the formation of lipid rafts. Similar to other ligand-receptor interactions that display such properties, these membrane changes can lead to endocytosis of the protein-artificial ligand complex.