Proteomics - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 397

plasma membrane is mainly composed of proteins, lipids and phospholipids, and
glycolipids. This microvillus plasma membrane contains a large number of enzymes
responsible for the hydrolysis of peptides and proteins.
8.4.1.5 Luminal and Membrane Absorption of Peptides and Protein
The drug absorption profile in the intestine are divided into different sections:
(1) cavital, (2) membrane contact, and (3) intracellular.
Cavital absorption occurs mainly in the small intestine and is catalyzed by
enzymes like trypsin, chymotrypsin, carboxypeptidase—all secreted by the pancreas
in the form of digestive juice. The aminopeptidase enzymes, located on the brush
border membrane of the intestine, facilitate membrane contact absorption followed
by intracellular metabolism.
8.4.2 Enzymatic Barriers to Peptide and Protein Drug Delivery
Proteases are found to be crucial in pathogenesis of insulin-dependent diabetes melli-
tus, various types of cancer, AD, and other diseases. The proteases that constitute enzy-
matic barrier at the mucosal route are not yet fully identified, and their role is not fully
elucidated. These include aminopeptidases, diaminopeptidases, post-aprolyl-cleaving
enzyme, angiotensin-converting enzyme (ACE), endopeptidase (a metalloproteinase),
and thiol protease enzyme. Nearly half of the aminopeptidases found in all mucosae
are in the nasal mucosa and ileal submucosa. Mitochondrial proteases degrade some
mitochondrial proteins, such as ornithine. Surface proteases are mainly responsible for
the hydrolysis of leucine and the enkephalin-type of proteins. Endopeptidases found
in axons and synaptic membranes inactivate Substance P and enkephalins. Numerous
studies have shown increased hydrolysis after oxidation in peptides like transferrin,
human serum albumin, superoxide dismutase, peroxidase, and others.
8.4.2.1 The Nature of the Enzymatic Barrier
The major sites of enzyme-induced protein degradation are the blood, liver, kidney,
and vascular endothelia due to an abundance of proteases. For instance, diaminopep-
tidase IV, ACE, and several other proteases that participate in angiotensin II degrada-
tion are present in the vascular endothelium.
8.4.2.2 Approaches to Circumvent Enzymatic Barrier
The approaches that are used to overcome or circumvent the enzymatic barrier to
elude premature protein metabolism have been discussed in detail in the next section.
�.4.2.2.1 Modification of Peptide and Protein Structure
8.4.2.2.1.1 Development of Orally Active Renin Inhibitors A number of methods
have been used to improve the stability of peptides to proteases. These methods include
(1) substituting unnatural amino acids, including D-amino acids, for L-amino acids in