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The synthesis and applications of the peptides are gaining increasing popularity as a result of the developments in biotechnology and bioengineering areas and for a number of research purposes including cancer diagnosis and treatment, antibiotic drug development, epitope mapping, production of antibodies, and vaccine design.
The use of synthetic peptides approved by the health authorities for vaccine, for cancer, and in drug delivery systems is increasing with these developments.
The aim of this book chapter is to review the recent developments in the use of peptides in the diagnosis of drug and vaccine systems and to present them to the reader with commercially available illustrations. Peptide Synthesis. The aim of this chapter is to review some applications of synthetic peptides providing a brief knowledge about peptide synthesis.
In the first part, information about the peptide synthesis was given in a very simple and readable format under the title of solid-phase peptide synthesis including a brief history, solid supports, linkers, protecting groups, and analysis method sections.
Then the synthetic peptide vaccine application of peptides was reviewed.
Current challenges in peptide-based drug discovery
After that, the topic of nuclear imaging-guided peptidic drug targets and labeling techniques and recent developments in therapy was discussed. In the last part, information about cell-penetrating peptides that can be used as molecular carries is mentioned with providing classification and cellular uptake mechanism of them.
The specific characters of peptides high bioactivity, high specificity, and low toxicity have made them attractive therapeutic agents. The synthesis of the peptides may provide sufficient material to enable further studies and to determine the structure-activity relationships or may provide discovery of new analogues with improved properties [ 1234567 ]. The peptides are able to synthesize in three methods: in a solution medium, on a solid support, or as a combination of the solid and the solution synthesis.
Although peptide synthesis is often carried out by the solid-phase method, the solution method was preferred by the pharmaceutical companies in the s and s [ 8 ]. In the solution medium synthesis method, except for the reversible protection of the N-amino group of the first amino acid or fragment, the orthogonal protection of carboxyl groups of the second amino acid or the fragment is needed. On the solid-phase method, the synthesis is carried out on a solid support, also called a resin. The peptide is separated from the resin after each amino acid in the peptide sequence is sequentially bound.
In the solid-phase technique, the peptide that bounded to the insoluble resin is separated without any significant loss during the washing or filtration of the resin. All reactions are carried out in a single reaction vessel, and possible losses are prevented during processes such as exchange and transfer of reaction vessels [ 9 ]. Another one is hybrid synthesis which is the composition of the solution and SPPS methods.
Herein, the peptide to be synthesized is obtained after the condensation from a solution of two or more suitable peptide sequences, which are obtained mainly by solid-phase synthesis [ 10 ]. The principle of peptide synthesis in the solid phase is quite simple. The peptide chain is attached to the stable solid phase.Welcome to Home Page of THPdb Therapeutic Proteins On therapeutic prespective, there is tremendous opportunity in terms of harnessing protein therapeutics to alleviate disease.
Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic — human insulin — about 30 years ago. The pharmaceutical industry is viewing therapeutic proteins with a renewed interest.
On going research is investigating a myriad of therapeutic peptides to study and improve their availability and efficacy. Group-wise Data Browsing: Modules under this section allow the users to retrieve data in classified manner. These modules allow users to browse peptide and protein therapeutics of different categories.
Web based tools integrated in THPdb allow users to perform similarity based search on sequence, structure or composition. Mobile Compatible Website: THPdb is built on a responsive template, compatible for desktop, tablet and smart phone. These templates are dynamic that fit content based on screen size of device. What is THPdb? These peptides have been classified into four categories according to their application, making it easy for the user to access them.
Therapeutic peptides are modified in different ways so as to alter their properties and then sold under different brand names by various companies. THPdb provides detailed description of such brands in a user-friendly way to enable quick access of relevant information on the peptides. All information compiled in this database has been extracted from research papers, patents, pharmaceutical company websites catering to product details, drugbank, US-FDA and others.Engineering synthetic metabolons: from metabolic modelling to rational design of biosynthetic devices View all 13 Articles.
Synthetic peptides have proven an excellent type of molecule for the mimicry of protein sites because such peptides can be generated as exact copies of protein fragments, as well as in diverse chemical modifications, which includes the incorporation of a large range of non-proteinogenic amino acids as well as the modification of the peptide backbone.
Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their utility for biological applications.
This article reviews recent advances by this and other laboratories in the use of synthetic protein mimics to modulate protein function, as well as to provide building blocks for synthetic biology. The detailed insight into the human genome does not in itself enable a comprehensive understanding of human protein function, health, and disease. In the post-genome era, an important challenge is the structural and functional analysis of the gene products, i.
Proteins play a major role in almost all biological processes, including enzymatic reactions, structural integrity of cells, organs and tissues, cell motility, immune responses, signal transduction, and sensing. All protein-mediated biological processes are based on specific interactions between proteins and their ligands. Therefore, exploring disease-associated protein—ligand and protein—protein interactions is essential to gain insight into the molecular mechanisms underlying diseases and other phenomena, as well as for the development of novel therapeutic strategies.
Molecules that present the binding sites of proteins, which are involved in a disease-associated protein—protein interaction, are promising candidates for therapeutic intervention. Such binding site mimetic molecules can be generated either through recombinant protein synthesis or by means of chemical peptide synthesis.
A specific advantage of synthetic peptides is that they can be generated as exact copies of protein fragments as well as in diverse chemical modifications, which include the incorporation of a large range of non-proteinogenic amino acids, as well as the modification of the peptide backbone.
Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their potential as drug candidates. Three conceptually different approaches are available for the design of protein-binding site mimetic peptides. These approaches are based on one or more of the following information about the proteins of interest: structure, sequence, and function.
In random combinatorial methods that are based solely on protein function, such as phage display Li and Caberoy, and synthetic peptide combinatorial libraries Houghten et al. A strategy termed peptide scanning is based on the synthesis of the entire protein sequence — or large parts of it — in the shape of short, overlapping peptides, which are then individually tested for binding to the respective partner protein Frank,enabling the identification of protein-binding sites.
The utility of this method, however, is largely limited to the identification of sequentially continuous binding sites, which are located in a protein sequence stretch of consecutive amino acids Figure 1 A. Structure-based design, finally, involves the design and generation of protein-binding site mimics based on the 3D structure of the protein—protein complexes Eichler, This structural information enables the design and generation of mimics of continuous, as well as of sequentially discontinuous protein-binding sites, which are composed of two or more protein segments that are distant in protein sequence, but brought into spatial proximity through protein folding Figure 1 B.
Mimicking such discontinuous protein-binding sites by synthetic peptides typically involves presentation of the respective protein fragments through a molecular scaffold Figure 1 B. Figure 1. Types of protein-binding sites illustrated by the HIV-1 envelope protein gp The epitope V3-loop tip, pink is located in a single sequence stretch and can be reproduced in a single peptide.
The binding site is located in three sequentially discontinuous segments of the protein sequence yellow, green, and red. In a mimetic peptides, these three fragments are presented through a molecular scaffold. Here, we review strategies for the use of synthetic peptides as protein mimics. Focusing on structure-based design, the potential of such peptides as drugs against diseases, such as viral and bacterial infections, cancer, as well as autoimmune diseases, are discussed.
A major advantage of chemical peptide synthesis, as compared to recombinant protein synthesis, is the extended set of amino acids and other building blocks that can be incorporated, which includes d -amino acids, as well as a wide range of non-proteinogenic amino acids Figure 2. While the recombinant synthesis of proteins containing non-proteinogenic amino acids is possible only through alternative codon usage Mehl et al. This opens the door to improved biological activity and peptide stability, as well as structural modifications.
Peptides composed of these amino acids are stable against proteolysis in vitro and in vivoas well as metabolism and degradation by microbial colonies Seebach et al. Figure 2. Building blocks for chemical peptide synthesis. A Amino acid derivatives with modified backbone length and side-chain orientation.
B Amino acid derivatives with modified aromatic side chains.
Synthetic Peptide Products Eligible for ANDA Submission – Maybe!
C Scaffolds for multivalent or discontinuous peptide presentation. Another possibility is the use of d -amino acids. While recombinantly synthesized peptides and proteins are typically composed entirely of l -amino acids, chemical peptide synthesis can also use d -amino acids, which has been shown to increase the proteolytic stability while maintaining biolocical activity when d -amino acids are introduced at defined positions of an antimicrobial peptide Hong et al.The central event of each signaling step in biology is biomolecular recognition.
Notwithstanding the importance of nucleic acids, carbohydrates, or lipids in ligand-target interactions, the effectors of most signal transduction processes are peptides. These can be fragments of proteins or stand-alone hormones, cytokines, toxins, antimicrobials, and many other types of peptides. At this point there is no good reason to classify peptides by the number of amino acid residues. We consider peptides as any polyamide or even biopolymer with ester, thioester, or otherwise modified backbone that can be made on a contemporary chemical peptide synthesizer.
The limit in size is greater than the arbitrary cutoff of 50 amino acids set up by the US Food and Drug Administration Carton and Strohl, for proteins and far exceeds that of biological recognition elements. While target recognition can occur with as low as a few residues Ertl et al.Oral Peptide Therapeutics - A Holy Grail or Quixotic Quest?
Thus, in principle synthetic peptides can be used to regulate almost all receptor responses. The high specificity and low toxicity of peptide drugs derive from their extremely tight binding to their targets. This is due to the large chemical space the side-chain variations of native amino acids cover.
Current databases estimate the total number of valid protein-ligand binding sites at Khazanov and Carlson, Calculation based on 17 variable residues Cys, Met, and Trp are significantly underrepresented in known ligandsshow that an 83,member tetrapeptide library can be prepared that will essentially cover all unique protein binding regions. As the median length of an active site is 11 amino-acid residues Khazanov and Carlson,designed ligands should also be longer.
While historically six-residue positional scanning could identify ligands of receptors or epitopes of monoclonal antibodies Dooley and Houghten,in our experience receptor agonists are 9—12 residue long Otvos et al. Antagonists acting on the same receptor binding sites are somewhat shorter vide infra.
If it is assumed that conformational preferences improve the binding kinetics but only rarely thermodynamics, then the tremendous specificity of side-chain combinations of peptides over six residues in length can be even further expanded by using non-natural residues.
Hundreds of appropriately protected and activated non-natural amino acid derivatives, ready for incorporation into synthetic peptides, are commercially available and indeed are frequently explored in peptide-based drug design.
Importantly, chemical biology has provided both backbone and side-chain combinations for exploring an enormous chemical space and is expected to supply peptide chemists with further building blocks suitable for identifying close-to-ideal agonists and antagonists of any biologically important target.
The selectivity of peptide drugs for their target is highlighted by the elevated success rate in clinical trials. According to a biotechnology report Thomas,of the 40 approved drugs infive However, in a recent report, the total number of peptide approvals between and was 19 Kaspar and Reichert, Due to the low number of drug approvals, any particularly successful year can bias the ratios significantly.
USP and Synthetic Therapeutic Peptides
According to another report, the overall success rate of all drugs entering clinical trials is just While peptides have traditionally been considered safe in Phase I clinical trials, the public perception is that they are less beneficial in late clinical trials when they are compared side-by-side with different types of treatment modalities.
It must be mentioned that peptides are less successful in oncology than in other applications. The biochemical processes that activated receptors directly or indirectly regulate include protein phosphorylation, nucleic acid transcription, ion transport, and a series of enzyme activities Yan and Wang, The debate centered on whether an rDNA peptide product and a synthetic peptide could be considered therapeutically equivalent.
Why, after all the years of considerations, is it now that OGD may permit such submissions? The guidance available here outlies some of the considerations relative to comparison of rDNA and synthetic peptide products:. Thus, a clean synthetic peptide product that has the same impurity profile as the RLD with no more of each impurity identified in the RLD and containing no new impurities other than those found in the RLD would have the greatest chance of approval success.
Characterization methods must be shown to be sensitive and accurate enough to permit a determination that the synthetic peptide is the same drug substance as the of the rDNA RLD. The guidance goes on to discuss the potential for immunogenicity issues that must be addressed by the ANDA applicant, and describes in further detail the scientific considerations for ANDAs for proposed generic synthetic peptide products including.
The guidance document suggests that the applicant seek counsel with the FDA through either controlled correspondence or a pre-ANDA meeting. Read the guidance document carefully and it you think you can meet the general requirements, It is still highly recommended the applicants proposing to submit such ANDAs seek advice from the FDA early in their development program to achieve the highest probability of success.
Also remember that just because the FDA has opened the door, approval may still be elusive if the data does not support approval. The guidance available here outlies some of the considerations relative to comparison of rDNA and synthetic peptide products: Similarity in impurity profile of the test and reference products show that, for each peptide-related impurity that is found in both the proposed generic synthetic peptide and the RLD, the level of such impurity in the proposed generic synthetic peptide is the same as or lower than that found in the RLD show that the proposed generic synthetic peptide does not contain any new specified peptide-related impurity that is more than 0.
The guidance goes on to discuss the potential for immunogenicity issues that must be addressed by the ANDA applicant, and describes in further detail the scientific considerations for ANDAs for proposed generic synthetic peptide products including Active ingredient sameness Impurity considerations The guidance document suggests that the applicant seek counsel with the FDA through either controlled correspondence or a pre-ANDA meeting.
And there are good reasons for this. However, it seems that this is beginning to change and that peptide therapeutics are growing in significance. As a matter of fact, peptides have become rather popular candidates for drugs. There is a rich source of peptide therapeutics; they can be mined from a variety of unicellular and multicellular organisms as well as from recombinant and chemical libraries.
Peptides offer a chemical diversity greater than that of any other class of biological molecule. Closely related analogues increase the diversity still further. The list of challenges is rather long. Challenge number one: peptides need to be delivered via injection because oral administration would lead to their degradation in the digestive tract. Challenge number two: they have a short half-life because they are quickly broken down by proteolytic enzymes in the digestive tract.
Challenge number three: they are relatively quickly cleared from the blood circulation by the liver and kidneys. Challenge number four: their hydrophilic nature prevents them to a large extent from getting past physiological obstacles.
Challenge number five: their pronounced conformational flexibility sometimes leads to a lack of selectivity, the activation of different cell structures and adverse effects. Many of the peptide drugs on the market are peptide hormones or peptide derivatives that stimulate hormone action. The number of peptide drugs being placed on the market has been increasing since A highlight and temporary peak was in when six peptide drugs were placed on the American market and five on the European market.
However, one of the drugs was withdrawn from the American market in An injectable GLP-1R agonist lixisenatide was approved by the European Commission for the treatment of type 2 diabetes in ; a synthetic peptide hormone afamelanotide with the ability to prevent the occurrence of skin cancers is currently undergoing EMA review and results are expected by mid As early as ina recombinant human parathyroid hormone Preotact with the potential to prevent vertebral fracture in postmenopausal women was placed on the market.
Around a dozen or so peptide drugs are currently undergoing advanced clinical testing. The peptide therapeutics that are already on the market target a broad range of indications and are administered either intravenously, subcutaneously, by inhalation and even orally linaclotide.
The majority of the peptide drugs that are currently undergoing clinical testing target indications in oncology and infectious diseases. Peptides undergoing clinical phase II testing frequently have a wide range of structural changes e.
The fact that peptides represent around half of all drug candidates in phase I clinical testing over the last two years is seen as evidence of the growing importance of peptide drugs for the treatment of human disease.
The pharmaceutical industry is working hard to find solutions that allow the oral administration of insulin in such a way that it is not rapidly degraded in the gastrointestinal tract.Therapeutic peptides occupy an interesting space along the molecular continuum between traditional small molecule drugs made through chemical synthetic routes and larger biologics made through recombinant DNA technology in living organisms.
Primarily made of amino acids strung together in a sequence, many therapeutic peptides are made through recombinant genetically-based means. While most small molecule drugs have a molecular weight of — Daltons, synthetic peptides can be quite large in comparison. Some peptides currently available on the U. An increasing number of these drugs are now being made synthetically. However, depending on the length of the peptide and its intended clinical indications, regulatory expectations for a particular peptide product can differ.
For small molecule drugs, regulations for products and their impurities are clearly articulated in guidances from the International Conference of Harmonization ICH.
There are also regulatory guidances for biologics —and now, a growing number of guidances for biosimilars are being developed.
The lack of guidances specific to therapeutic peptides has resulted in a regulatory vacuum and presents challenges for manufacturers of these products. Until more recently, manufacturers hesitated making peptides synthetically and preferred recombinant approaches. Cost and quality control challenges have been major drivers behind this preference. Understanding how to control for impurities when transitioning from a recombinant route of manufacture to a synthetic one is also critical for the product maker.
In recombinant peptides—even those that are longer and made of more complex amino acids chains—residual DNA and proteins from the host cell used to make the product are some of the most critical impurities to control in the final product.
With synthetic peptides, impurities can come from the raw materials used to make the product or can be process-related based on the particular approach to synthesis. Therefore, process impurities from synthetic peptides can vary from manufacturer to manufacturer. In both recombinant and synthetic peptides, regular product variants in the form of degradants must also be controlled. In spite of these challenges, manufacturers continue to pursue synthetic peptide approaches.
In general, any therapeutic product made through a recombinant technology must go through the Biologics License Application BLA process. However, some older biologics that are proteins—like insulin—have been approved through the traditional New Drug Application NDA pathway primarily intended for small molecule drugs.
An FDA policy that will go into effect in will require that any protein made of more than 40 amino acids and is recombinant in makeup will be required to go through the BLA route.
However, the FDA definition of a peptide is a product with less than amino acids and is made through chemical synthesis; thus, a product that falls within this definition can be approved through an NDA, with fewer regulatory hurdles. A product approved through the biosimilar pathway will need to overcome additional regulatory hurdles in order to be considered interchangeable with its reference product. Thus, products made through chemical routes can immediately enter the innovator market once approved.
Combined with an increasing number of technological advances that make a synthetic route more viable for manufacturers, these factors are fueling a growing interest in synthetic therapeutic peptides. Inthe U. Pharmacopeial Convention USP hosted a workshop for manufacturers and regulators involved in synthetic therapeutic peptides. In addition, questions emerged at the workshop about regulatory expectations for peptides that are transitioning from recombinant routes to synthetic approaches.