Peptide+Targeting+and+Delivery


 * Basic Description **

Following the long and extremely complicated process known as protein synthesis comes the lesser-discussed process called protein targeting. Otherwise known as protein sorting, protein targeting is an essential biological mechanism that determines the final destinations of the proteins that our bodies mass produce. Proteins can be sent to anywhere within the cell, to the plasma membrane, or even to the exterior of the cell. What determines where the protein will go is the genetic information within the protein itself, something called a target peptide.

Comprised of anywhere between 3-70 amino acids, a target peptide is a short chain that specifically codes for the final destination of a protein.

After translation, there are two main sets of options for protein relocation: one set for those proteins synthesized by ribosomes that remain suspended in the cytosol, and one set for proteins synthesized by ribosomes that are attached to the membranes of the endoplasmic reticulum. Therefore, the first decision that must be made as a ribosome begins to translate an mRNA into a polypeptide is whether to remain free in the cytosol or to bind to the ER.

If a growing peptide has a signal sequence on it, it proceeds to enter the endoplasmic reticulum. The signal sequence consists of the first portion of the elongating polypeptide chain, and typical signal sequences contain 15–30 amino acids.

If a signal sequence is present, translation ceases, and signal recognition particles bind to it. Then, a ribosome and it’s nascent polypeptide binds to the receptor on the surface of the endoplasmic reticulum. When the SRP leaves, translation then commences. The ER expels the growing polypeptide through a pore and it then flows into the ER lumen. Molecular chaperones, which are present in the lumen, bind to the growing chain and assist it in folding into a tertiary structure. In order to turn the chain into the final product, a glycoprotein, a sugar residue is usually added to the protein during the last step, glycosylation.

[i]

After synthesization is complete, the proteins are transported to the Golgi apparatus through ER-derived transport vesicles. Further steps of glycosylation may occur within the Golgi apparatus. The exact pattern of glycosylation determines the final destination of the proteins.

There are two options. These are:
 * proteins glycosylated with residues of mannose-6-phosphate will leave the Golgi in transport vesicles that eventually fuse with [|lysosomes]
 * proteins that do not receive this marker, leave in transport vesicles that eventually fuse with the plasma membrane
 * o integral membrane proteins that become exposed at the surface of the cell (forming receptors and the like) and
 * o proteins in solution within the transport vesicle. These are discharged from the cell. This secretory process is called [|exocytosis].

If the newly synthesized protein remains within the cytosol, it can go on to perform vital functions for a range of organelles, including the cytosol itself, the nucleus, mitochondria, chloroplasts, chloroplasts (in plants), and peroxisomes. [i]

Peptide targeting and delivery is a quintessential aspect of cellular biology on many different levels. Without it, the proteins that our cells spent valuable energy producing would no longer have a final destination, and thus would not be utilized. Because almost every bodily function depends upon the administration and regulation of proteins, it would be impossible to exist without proper peptide targeting.
 * <span style="font-family: 'Times New Roman',Times,serif;">Relevance to Cellular Physiology **

<span style="font-family: 'Times New Roman',Times,serif;">Recently, there has been much progress made in the way of utilizing peptide targeting in the treatment of human cancer. Although antibody targeting is the more common alternative, it has major limitations, two of which include their large size and their nonspecific uptake. These problems lead to poor tumor penetration of antibody pharmaceuticals and dose-limiting in order to not poison the liver and bone barrow. However, peptides do not suffer from these issues. In the last decade, researchers have discovered that cell surface peptides are useful for cancer targeting, and can be used as a new revolutionary approach to cancer therapy.[ii]
 * <span style="font-family: 'Times New Roman',Times,serif;">Current Research Pertaining to Peptide Targeting and Delivery **

<span style="font-family: 'Times New Roman',Times,serif;">In the article //Identification of homing peptides using the in vivo phage display technology//, the scientists of the Molecular Cancer Biology Research Program of the University of Helsinki sought to use that in-vivo phage display technology to identify peptides that specifically home to tumor lymphocytes. These peptides recognize the difference between lymphatic vessels in one set of tumors from another, and can also differentiate the lymphatic vasculature of a premalignant lesion from that of a full-blown tumor. By demonstrating that there is sufficient access to these peptides, the scientists are also proving that it is not only possible to directly target tumor cells, but to also use such peptides to determine tumor stage-specific differences in the lymphatic vessels. Armed with this information, the delivery of therapeutic drugs and imaging agents will be more accurate than ever before, and will allow for a greater percentage of success with regards to cancer treatment. [iii]
 * <span style="font-family: 'Times New Roman',Times,serif;">Relevant Articles **

<span style="font-family: 'Times New Roman',Times,serif;">A second article, titled //Family of pH (low) insertion peptides for tumor targeting//, describes new techniques to target cancerous cells through the detection of surrounding acidic extracellular environments with peptides. In recent years, scientists have noticed a particular trend about cancerous cell- increased extracellular acidity as a result of acidosis. Subsequently, acidic environments have been used as a universal marker for cancer imaging and the delivery of therapeutic molecules in the past. In order to make targeting even more tumor specific, scientists have utilized a new approach for the targeting of acidic tissue using the pH—sensitive folding and trans membrane insertion of pH insertion peptide. By fine-tuning the design, scientists can alter tumor targeting, distribution in organs, and blood clearance. And so, this article expands on the importance of peptide targeting in cancer treatment by presenting the opportunity to alter how the tumors are targeting, and the amount of blood that reaches a growing tumor mass. By altering the physiology of the cell membrane of a cancerous cell, researchers will potentially be able to halt the growth of such cells before they have the opportunity to cause real damage. [iv]

<span style="font-family: 'Times New Roman',Times,serif;">Lastly, the article //Peptide targeting of adenoviral vectors to augment tumor gene transfer//, the scientists of the University of Texas explored the use of adenovirus serotype 5 as a vector for delivering genetic material to cancer cells for imaging and therapy. To further the mission, scientists have started inserting peptide sequences into the capsid proteins to better improve targeting and reduce the effects in non-target tissues. They also examined the ability of peptide-targeted vectors to infect several tumor cell types, both in vitro and in vivo by genetically incorporating these peptides into a surface loop of the fiber capsid protein to construct targeted adenovirus vectors. This study showed results that prove that doing so results in no effective changes, and that simply inserting the peptides into fiber is more poignant. Overall, this study proved that whether in vivo or in vitro, it is of high importance that ligand: receptor interactions have a high affinity towards one another in order to achieve sufficient targeting. [v]

<span style="font-family: 'Times New Roman',Times,serif; line-height: 1.5;">[i] Kimball, John. "Protein Kinesis." RCN D.C. Metro | High-Speed Internet, Digital Cable TV & Phone Service Provider. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/ProteinKinesis.html (accessed October 14, 2013). <span style="font-family: 'Times New Roman',Times,serif;">[ii] Aina, Olulanu H., Thomas C. Sroka, Man-Ling Chen, and Kit S. Lam. "Therapeutic Cancer Targeting Peptides." Biopolymers66, no. 3 (2002): 184-199. http://dx.doi.org/10.1002/bip.10257 (accessed October 13, 2013). [iii] Rivinoja, A, and P Laakkonen. "Identification of homing peptides using the in vivo phage display technology.."//Methods in Molecular Biology// 683 (2011): 401-415. http://www.ncbi.nlm.nih.gov/pubmed/21053146 (accessed October 14, 2013). [iv] Weerakkody, D, A Moshnikova, MS Thakur, V Moshnikova, J Daniels, DM Engelman, OA Andreev, and YK Reshetnyak. "Family of pH (low) insertion peptides for tumor targeting.."//Proceedings of the National Academy of Sciences// 110, no. 15 (2013): 5834-5839. http://www.ncbi.nlm.nih.gov/pubmed/23530249 (accessed October 14, 2013). [v] Ballard, EN, VT Trinh, RT Hogg, and RD Gerard. "Peptide targeting of adenoviral vectors to augment tumor gene transfer.." //Cancer Gene Therapy- Nature//19, no. 7 (2012): 476-488. http://www.ncbi.nlm.nih.gov/pubmed/22595794 (accessed October 13, 2013).