From Production of Peptides in Milligram Amounts for Research to Multi-Tons Quantities for Drugs of the Future
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.
Available from: Michael Firer
- "There are now several dozen peptide therapeutics approved for clinical use and the market for therapeutics peptides is estimated to reach $11.5billion by 2013 (BioNest). Over the last decade or so, processes in peptide manufacture have considerably evolved, partly due to the experience of scaling up production from milligram to multi-ton levels [143,144]). These requirements have generated important improvements in both technical and cost efficiency aspects of process design, manufacturing capacity and peptide synthesis . "
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ABSTRACT: Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients.
Available from: Bok Sil Hong
- "*, **, 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). "
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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.
Available from: Fernando Albericio
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