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.
[Show abstract] [Hide abstract] ABSTRACT: In order to surpass the problem of genetic variability of hepatitis C virus envelope proteins during vaccine development, we used the so-called "reverse vaccinology"approach - "from genome to vaccine". Database of HCV protein sequences was designed, viral genome analysis was performed, and several highly conserved sites were revealed in HCV envelope proteins in the framework of this approach. These sites demonstrated low antigenic activity in full-size proteins and HCV virions: antibodies against these sites were not found in all hepatitis C patients. However, two sites, which contained a wide set of potential T-helper epitope motifs, were revealed among these highly conserved ones. We constructed and prepared by solid-phase peptide synthesis several artificial peptide constructs composed of two linker-connected highly conserved HCV envelope E2 protein sites; one of these sites contained a set of T-helper epitope motifs. Experiments on laboratory animals demonstrated that the developed peptide constructs manifested immunogenicity compared with one of protein molecules and were able to raise antibodies, which specifically bound HCV envelope proteins. We succeeded in obtaining antibodies reactive with HCV from hepatitis C patient plasma upon the immunization with some constructs. An original preparation of a peptide vaccine against hepatitis C is under development on the basis of these peptide constructs.0Comments 0Citations
- "In contrast to synthesis using tertbutyl(oxycarbonyl )(BOC)-amino acid derivatives it does not require the use of such strong acid as HF to cleave the synthesized peptide from the support at the end of the process. FMOC-amino acids are preferably used in large-scale peptide synthesis that may yield tens and even hundred kilograms of peptides (Bruckdorfer et al., 2004). Since it is difficult to obtain long peptides (exceeding 30 residues) with good yield and separate them from contaminants differing by 1—2 residues, such peptides are synthesized as 2—3 fragments with protected side chain functional groups and then these fragments are linked together (in solution) into a single molecule (Mitsuaki et al., 1987; Rinnova et al., 1999). "
[Show abstract] [Hide abstract] ABSTRACT: Peptides are becoming an important class of molecules in the pharmaceutical field. Closely related peptide-impurities in peptides are inherent to the synthesis approach and have demonstrated to potentially mask biomedical experimental results. Quorum sensing peptides are attracting high interest in R&D and therefore a representative set of quorum sensing peptides, with a requested purity of at least 95.0%, was evaluated for their purity and nature of related impurities. In-house quality control (QC) revealed a large discrepancy between the purity levels as stated on the supplier's certificate of analysis and our QC results. By using our QC analysis flowchart, we demonstrated that only 38.0% of the peptides met the required purity. The main compound of one sample was even found to have a different structure compared to the desired peptide. We also showed that the majority of the related impurities were lacking amino acid(s) in the desired peptide sequence. Relying on the certificates of analysis as provided by the supplier might have serious consequences for peptide research and peptide-researchers should implement and maintain a thorough in-house QC.0Comments 5Citations
- "Interfering with this bacterial quorum sensing pathway might open interesting application perspectives. Chemical peptide synthesis for medicinal purposes has become economically viable . The possibility to produce small, medium (5–20 residues) to large (20–50 residues) peptides has evolved dramatically, hereby frequently outperforming the biotechnological approaches as they are known to date . "
- "Although these compounds generally have a good performance, sometimes they could lead to unsatisfactory results in terms of yield and purity of target compounds obtained. They are not so inexpensive, and often with low effectiveness due to the target bond formation [20,21]. They also activate some secondary reactions during the process of the desired bond formation like dehydration of Gln and Asn CONH 2 function under the influence of DCC . "