Ion-transporting peptide

There is growing evidence implicating Na+-dependent solute transporters and intracellular as well as extracellular Ca2+ in the physiological regulation of the paracellular pathway [81,203,204], Such modulation of paracellular permeability is especially important for drugs such as peptides and oligonucleotides that exhibit poor permeability characteristics across both the cornea and the conjunctiva [150,152,154,155], In addition, ion transporters such as Cl and Ca2+ channels have been implicated in macromolecular transport (see Sections IV.B.2 and IV.B.4). In the following discussion, some key ion transport processes and their possible roles in solute transport across epithelial tissues are summarized. 

The bonding of K+ and Na+ to A-methylacetamide is of interest64 in studies of the interaction of these ions with peptides and proteins, and particularly studies of the ion transport through transmembrane channels such as the gramicidin channel. Roux and Karplus35 have used the complexation of the given alkali ion with two N-methylacetamide molecules and two water molecules as a model for interactions occurring in transmembrane channels. 

Structure of a Peptide Antibiotic from Bacillus brevis Extracts from the bacterium Bacillus brevis contain a peptide with antibiotic properties. This peptide forms complexes with metal ions and apparently disrupts ion transport across the cell membranes of other bacterial species, killing them. The structure of the peptide has been determined from the following observations. 

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

Neuropeptides Y (NFY) and YY are 36-residue amidated peptides that are members of the pancreatic polypeptide (PP) family (Fig. 30-5). NPY is produced both in the peripheral nervous system and in the brain,110 134 where it is one of the most abundant neuropeptides. Another member of the PP family is semi-nalplasmin, a regulator of calcium ion transport in bovine sperm.135 NPY is best known for its stimulation of appetite. It also inhibits anxiety and increases memory retention. It has a vasoconstrictive effect on blood vessels, participating in cardiovascular regulation.136 137 Peptide YY is formed in endocrine cells of the intestine, while NPY is formed in neurons of the parasympathetic system.138 Both participate in regulation of fluid and electrolyte secretion. Both are found in other vertebrate species.139... 

Cyclic a-peptides have seen applications in many areas of chemistry. It is therefore natural that interest in cyclo-(3-peptides also exists. In addition to examples of cyclic a-peptides with interesting biological activity, there have been examples of cyclo-a-peptides 51 which can act as nanotubes and ion transporters (Scheme 16).f3334l Although little evidence has yet been published for biological activity of (3-peptides, Seebach and co-workers[35i have shown that the cyclic (3-peptides 52 do exhibit some of the tube-like properties associated with the cyclic a-peptides built from alternating (R)- and (5)-amino acids. 

Early studies of peptides isolated from microbial sources and possessing antibiotic activity led to the discovery of some a-amino acids not normally found in proteins. The peptides containing these nonproteinogenic, but natural a-amino acids exhibit helical structures which act as channels for transmembrane ion transport 32 Formation of a- or 310-helices in these peptides was ascribed to the unique geometry of these residues and their present use in the induction of these conformations is now widely established. 

Along the same lines, an artificial ion channel was prepared by Montal and coworkers [33] using the TASP approach. In their work, a four a-helix bundle structure 67 was synthesized on a peptide template. The ion transport ability was well characterized and 67 turned out to have several similarities with the natural acetylcholine receptor channel they were mimicking. 

Transmembrane channels represent a special type of multi-unit effector allowing the passage of ions or molecules through membranes by a flow or site-to-site hopping mechanism. They are the main effectors of biological ion transport. Natural and synthetic peptide channels (gramicidin A, alamethicin) allowing the transfer of cations have been studied [6.66-6.68]. 

Another way to assess ion channel conductance is to use artificial phospholipid vesicles (liposomes) as cell models. These structures (described in more detail in the next chapter) are commonly used to transport vaccines, drugs, enzymes, or other substances to target cells or organs. The vesicles, which are several hundred nanometres in diameter, do not suffer from interference from residual natural ion channel peptides or ionophores, unlike purified natural cells. A liposome model was used to test the ion transport behaviour of the redox-active hydraphile 12.36. The compound transports Na+ and the process can also be monitored using 23Na NMR spectroscopy.26 The presence of the ferrocene-derived group in the central relay allows the ion transport to be redox-controlled - oxidation to ferrocinium completely prevents Na+ transport for electrostatic reasons. Some representative data from a planar bilayer measurement is shown for hydraphile 12.36 in Figure 12.16. 

Figure 7.1 The general mode of action of ionophores in ion transport, (a) A channel formed by two gramicidin A molecules, N-terminus to N-terminus. (b) The sequence of events in the operation of a carrier ionophore such as valinomycin. Valinomycin is a cyclic peptide consisting of three repeating units with the structure shown...

Model systems have been developed for many of these ion-transport mechanisms in the context of bioorganic chemistry. Examples are the cyclic peptides, described by M. R. Ghadiri et al., that have antibiotic activity similar to that of ionophores, a property that is most probably caused by the ability of these peptides to self-assemble inside biological membranes into channels [1], Other compounds able to induce the formation of membrane pores are the bouquet-molecules introduced by J.-M. Lehn [2]. Artificial / -barrels have been developed by S. Matile s group [3]. Many host molecules used in bioorganic chemistry can serve as carriers for ions across membranes and have even made possible the development of systems with which active ion transport can be achieved [4]. 

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