Peptide therapeutics: current status and future directions


By Keld Fosgerau and Torsten Hoffmann (Drug Discovery Today ahead of print)

In recent years peptide therapeutics have emerged as a novel therapeutics due to good safety, tolerability and efficacy. Also the production cost of peptides is lower than other technologies, like small molecules or protein production. However, there are some pitfalls in peptide therapeutics such as reduced choice of route of administration, poor high-life in plasma or higher degradation rate by oral route. Consequently, there is an important focus on new approaches to improve the use of peptides in pharmaceutical research. In this paper the authors give a summary of the most important new approaches and developments in peptide therapeutics.
In the last ten years, some companies have successfully launched peptides as new drugs, such as Lupron™ from Abbot Laboratories (prostate cancer treatment), gaining worldwide sales of more than US$2.3 billion in 2011. Sanofi with the drug Lantus™ (Diabetes treatment) reached US$7.9 billion in 2013. By last year the FDA had approved more than 60 peptides drugs on the market and currently there are more than one hundred peptides drugs currently in clinical trials, predicted to reach sales of US$25.4 billion in 2018. The main disease areas in which peptides are used are metabolic diseases and oncology.
In order to obtain better peptide therapeutics it is necessary to make a rational peptide drug design to improve the physicochemical properties of natural peptides. The strategies include substitution of amino acids (alanine scan), small focused libraries and structure-activity relation to identify essential amino acids and possible substitution (Figure 1).

In recent years peptide therapeutics have emerged as a novel therapeutics due to good safety, tolerability and efficacy. Also the production cost of peptides is lower than other technologies, like small molecules or protein production. However, there are some pitfalls in peptide therapeutics such as reduced choice of route of administration, poor high-life in plasma or higher degradation rate by oral route. Consequently, there is an important focus on new approaches to improve the use of peptides in pharmaceutical research. In this paper the authors give a summary of the most important new approaches and developments in peptide therapeutics.
In the last ten years, some companies have successfully launched peptides as new drugs, such as Lupron™ from Abbot Laboratories (prostate cancer treatment), gaining worldwide sales of more than US$2.3 billion in 2011. Sanofi with the drug Lantus™ (Diabetes treatment) reached US$7.9 billion in 2013. By last year the FDA had approved more than 60 peptides drugs on the market and currently there are more than one hundred peptides drugs currently in clinical trials, predicted to reach sales of US$25.4 billion in 2018. The main disease areas in which peptides are used are metabolic diseases and oncology.
In order to obtain better peptide therapeutics it is necessary to make a rational peptide drug design to improve the physicochemical properties of natural peptides. The strategies include substitution of amino acids (alanine scan), small focused libraries and structure-activity relation to identify essential amino acids and possible substitution (Figure 1).

thalia1

Figure 1

Figure 2 highlights the advantages and issues associated with peptide based drug discovery

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Figure 2

The new approaches currently used in development for peptides are:
Multifunctional and cell penetrating peptides
Peptide drug conjugates
Alternative routes of administration
The majority of current peptide drugs are injectables with a lesser number of oral drugs, such as cyclosporine (Neoral™) and desmopressin (Minirin™). The development of oral delivery is expected to increase due to it being more suitable for the patient. However, one of the difficulties of oral peptides is acidic/enzymatic degradation by the gastrointestinal tract and intestinal mucosa. New approaches for oral peptides to avoid degradation includes; stabilizing the secondary structures by stapled peptides, hydrophobic faces, cyclization, N-methylation, and intramolecular bonds. Some companies working in this research are; Ra Pharma, Peptidream, Cyclogenix and Bycycle Therapeutics.
Current multifunctional peptides are antimicrobial peptide drugs that have additional functions like immune stimulation and wound healing. The most focused research in multifunctional peptides is the glucagon-like peptide-1 (GLP-1) agonist with several currently in clinical trials.
Another major strategy for novel peptide therapeutics in the field of oncology, is the conjugation of peptides with a higher efficacy and safety properties. Nowadays there are more than 20 peptide conjugates in clinical trials.
Some examples of modifying peptides using a rational design to help improve the physicochemical properties are; the introduction of stabilizing α-helixes, salt bridge formations or other chemical modifications, such as lactam bridges. It is really important to avoid the enzymatic degradation of peptides due to the short half-life in plasma. Some important biotechnologies companies (Pepscan and Aileron Therapeutics) are working towards protecting peptides against enzymatic cleavage by different approaches, such as insertion of a structure inducing probe (SIP)-tail, lactam bridges, stapling/cipling peptide sequences or by cyclization.
One common strategy for extending half-life of peptides is binding them to albumin as a vehicle, to obtain a peptide requiring less frequent administration. Another approach for increasing plasma half-life is using Polyethylene glycol (PEG)-ylation to limit globular filtration and reducing the elimination of peptides; however, PEG had some concerns related with safety and tolerability. A new “smart” formulation technology by Intarcia is an implantable device that delivers peptide from a dry reservoir using an osmotic pump system. The last example gives a new and innovative way of delivering peptide therapeutics in a better, easy and comfortable method for the patient.
With the potential sale market, excellent safety, tolerability and efficacy in humans peptide therapeutics is an attractive approach for drug research and development.

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