R O Hydrophllic head groups c-N-C-C- N-formyl group H H H. Surface of liquid R 0= o=S- N-acetyl C-N-C-C- Amphipathic molecules Monolayer group CH3 нн Hydrophoblc tall groups Mlcelle R C-terminal -N-C-C amide нн NH, AQUEOUS PHASE A FIGURE 5.12 Groups that may block N- or C-temini in proteins. Blocking of the N-terminus with a formyl or acetyl group is more common than modifying the C-terminus to an amide. Blayer vesicle (a) Structures formed in water. Structures that can form when amphipathic substances are mixed with water include a monolayer on the water surface, a micelle, and a bilayer vesicle, a hollow sphere with water both inside and out. In each case, the hydrophilic head groups are in close contact with the aqueous phase, whereas the hydrophobic tails associate with one another. Dodecanoate lon (an lonized fatty acld) Dodecyl sulfate (a detergent) Phosphatidylethanolamine (a phosphollpld) A FIGURE 2.15 Amphipathic molecules. These three examples illustrate the dual nature of amphipathic molecules, which have a hydrophilic head group attached to a hydrophobic tail. Veslcle (b) Vesicle formation. When phospholipids are mixed with water, the amphipathic molecules aggregate to form films similar to biological membranes. Agitation causes the film to break up into vesicles. A FIGURE 2.16 Interactions of amphipathic molecules with water. O=-o-
Despite the fact that many peptides have critical physiological functions
(e.g., as hormones, neurotransmitters, antibacterial toxins), they are not considered to be ideal as drugs. The following questions illustrate some of the issues that limit the use of peptides as therapeutics.
(a) Insulin is a peptide therapeutic used to manage Type 1 diabetes, which
affects more than 20 million people worldwide according to the International Diabetes Federation. A significant limitation to the broad distribution and use of insulin to treat Type 1 diabetes is the fact that it must be administered by injection rather than orally. Why is insulin administered by injection and not orally?
(b) Many of the D-amino acids found in nature have been discovered in
bacterially produced peptides that have antibiotic properties. Bacteria
secrete these peptides into their environments to kill competitor bacteria
and thereby gain a selective advantage. Given your answer to part (a) of
this question, what potential advantages might D-amino acids confer to a
secreted peptide toxin?
(c) As a class of
(i.e., few peptides readily cross the membrane bilayer). This limits most
peptide-based drugs to targets that are on the surfaces of cells (rather
than in the cytoplasm or the nucleus). Review the information as shown propose a reason that most peptides are not likely to cross the membrane bilayer.
(d) Does as shown suggest a strategy for increasing the membrane permeability of peptides?
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