Proteomics - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 398

the primary structure, (2) introducing conformational modification, (3) changing the
direction of the peptide backbone and reversing the chirality of each amino acid, and
(4) acylating or alkylating the N-terminus or altering the carboxy terminus by reduction
or amide formation. Renin is an aspartic acid protease produced in the juxtaglomerular
apparatus of the kidney, and it is the first major rate-limiting agent in the biosynthe-
sis of angiotensin II. This protease acts upon the zymogenic angiotensinogen, converts
the latter to angiotensin I, and then to an octapeptide angiotensin II by the ACE. The
angiotensin II produced is, in turn, responsible for stimulating the release of adrener-
gic hormones and neurotransmitters that stimulate cardiac functions. Inhibition of renin
may facilitate reversal of pathophysiological changes associated with hypertension. A
knowledge of renin inhibitors can prove to be a major step in designing a class of thera-
peutically active antihypertensive agents.
�.4.2.2.2 Coadministration with Protease �nhibitors: Protease �nhibitors
as Drugs
Concomittant administration of proteins with protease inhibitors has been success-
ful in promoting the oral absorption of the peptides pentagastrin and PHPFHLFVF
(a nonapeptide renin inhibitor) and of the proteins. In 1959, Danforth and Moore [32]
studied the role of diisopropyl fluorophosphates, a serine proteinase inhibitor, in pre-
venting insulin from getting hydrolyzed, and thereby showed significant increase in
bioavailability of orally given insulin. Another effective protease inhibitor was apro-
tinin, which protects RNAase from proteolysis. Efficacy of aprotinin was enhanced
in the presence of bile salts like deoxycholate and cholates.
Apart from above mentioned strategies adopted to surpass the enzymatic barri-
ers, efforts are being made to develop pharmaceutical formulations and novel drug
delivery systems that can circumvent enzymatic barrier and enable the protein to
reach the target site for example protein entrapped in vesicular carriers, like lipo-
somes, nanoparticles, microparticles. Here, the peptide or protein drug is entrapped
within a vesicular or delivery system to protect the protein from enzymatic action as
well as to improve its target specificity. Ongoing attempts are being made to develop
liposomes, emulsion, nanoparticles, and soft gelatin capsules to improve insulin and
other protein delivery.
One such smart and highly sophisticated device has been designed by Saffran
[33] . This system is composed of an azo cross-linked copolymer of styrene and
hydroxymethylmethacrylate that coats the protein and is unaffected throughout
the gastrointestinal tract until it arrives at the ilorectal junction. The azoreductase
enzyme expressed by colonic microflora reduces the azo bond, causing the polymer
to disintegrate and release the intact protein, and facilitates its absorption.
8.4.3 Intestinal Epithelial and Vascular Endothelial Barriers to Peptide
and Protein Delivery
In order to elicit or evoke a therapeutic response, a drug has to traverse a number
of biological membranes and compartmental barriers. The epithelial and vascular
endothelial membranes play a pivotal role in drug delivery and absorption, as well