From Production of Peptides in Milligram Amounts for Research to Multi-tons Quantities for Drugs of the Future
ABSTRACT Peptides are key to modern drug discovery. This article reviews the requirements for bulk production of peptides and how it affects research and production of smaller scales. Peptides, as modern drugs, are currently produced in millions in mg-scale for research purpose, in order to better understand the function of biological systems. Some newly discovered sequences form the basis of modern drugs and are now produced in multi-tons. The most popular example is the T-20 peptide (Fuzeon), which is the first peptide produced at such scale by a combination of solid phase and solution phase methodologies. This particular peptide sequence has the ability to dock on the surface of the HIV virus and block the virus from entering into a human blood cell, helping patient life conditions. A multi-ton scale production was made necessary based on the high number of patients, the socio-economical importance of the disease and the strong support by governmental institutions such as the FDA. Fuzeon is the first peptide-based drug that is produced in multi-tons on solid support. This had revolutionary effects on the whole peptide synthesis techniques in general including the production of the starting materials. It also had a positive impact on the cost-effectiveness of peptides for research, as the standard technique for producing peptides in research quantities is solid phase chemistry. The decrease of the cost of all starting materials will lead to an increase of the number of produced peptides, which will certainly bring new interesting and effective sequences to be used as novel drugs.
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- "*, **, and *** mean P ＜ 0.05, P ＜ 0.01, and P ＜ 0.001, respectively. (Bruckdorfer et al., 2004; Park et al., 2009). Synthetic combinatorial peptide libraries have been utilized successfully to discover bioactive peptides such as antimicrobial peptides (Blondelle et al., 1996), ligands for cell surface receptors (Bae et al., 2003), protein kinase inhibitors and substrates (Wu et al., 1994; Songyang et al., 1995), and peptide mimotopes of receptor binding sites (Bracci et al., 2001). "
ABSTRACT: Angiogenesis is critical and indispensable for tumor progression. Since VEGF is known to play a central role in angiogenesis, the disruption of VEGF-VEGF receptor system is a promising target for anti-cancer therapy. Previously, we reported that a hexapeptide (RRKRRR, RK6) blocked the growth and metastasis of tumor by inhibiting VEGF binding to its receptors. In addition, dRK6, the D-form derivative of RK6, retained its biological activity with improved serum stability. In the present study, we developed a serum-stable branched dimeric peptide (MAP2-dRK6) with enhanced anti-VEGF and anti-tumor activity. MAP2-dRK6 is more effective than dRK6 in many respects: inhibition of VEGF binding to its receptors, VEGF- and tumor conditioned medium-induced proliferation and ERK signaling of endothelial cells, and VEGF-induced migration and tube formation of endothelial cells. Moreover, MAP2-dRK6 blocks in vivo growth of VEGF-secreting colorectal cancer cells by the suppression of angiogenesis and the subsequent induction of tumor cell apoptosis. Our observations suggest that MAP2-dRK6 can be a prospective therapeutic molecule or lead compound for the development of drugs for various VEGF-related angiogenic diseases.Experimental and Molecular Medicine 07/2010; 42(7):514-23. DOI:10.3858/emm.2010.42.7.052 · 2.46 Impact Factor
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ABSTRACT: BY ELECTRON and optical microscopic techniques, the precipitation out of the original solid solution of a phase based on Ni3Al has been observed in the metal films condensed from the alloy Evanohm. A precipitation clustering of solute atoms causes a slight increase in the film resistivity. This is followed by a large decrease in resistivity as the solute content of the solvent or matrix is depleted by the growth of the solute rich precipitates. The rate of these processes has been observed to depend on the thickness of the film, with the thinnest films aging fastest. The oxidation of these films has been studied using electron microscopy to identify the reaction and using a quartz crystal microbalance to determine the reaction kinetics. Prior to precipitation, a uniform Cr2O3 oxide layer grows with a limiting thickness, saturating form of kinetics. This is typical of a case where a retarding electric field is created in the oxide layer by the migration of the charged species which eventually halts the diffusion or oxidation process. Later, after clustering and precipitati6n has occurred, a particulate oxide identified as NiO grows with kinetics proportional to the cube of time. This particulate oxide grows in the solute-depleted portion of the matrix.Physics of Failure in Electronics, 1964. Third Annual Symposium on the; 10/1964