At present, more than 7000 natural peptides have been identified, and these peptides play a key role in human physiology, including hormones, neurotransmitters, growth factors, ion channel ligands, or anti infection.

In the past decade, peptides have been widely used in the field of medicine and biotechnology, and the research of therapeutic peptides is undergoing a commercial Renaissance.

Application beyond GLP-1

From cancer to diabetes, and to orphan drugs, even infectious diseases and inflammation; different from the traditional injection drug alternative drug delivery methods, further expand the space of peptide drugs in therapeutic peptide drugs, there is no lack of "blockbuster". For example, leuprorelin acetate, a polypeptide drug used by Abbott to treat prostate cancer, had global sales of more than $2.3 billion in 2011; Sanofi's sales (between polypeptide drugs and small molecular biological drugs) reached $7.9 billion in 2013. At present, there are more than 60 peptide drugs approved by FDA for marketing, which is expected to increase significantly; there are about 140 peptide drugs in clinical trials, and more than 500 in preclinical studies.

In terms of value, it is predicted that the global peptide drug market will increase from US $14.1 billion in 2011 to about US $25.4 billion in 2018. Among them, the innovative peptide drug market will increase from $8.6 billion in 2011 to about $17 billion in 2018.

A recent example of innovative peptide drugs is the glucagon like peptide-1 (GLP-1) agonist for the treatment of type 2 diabetes mellitus (T2DM), the most prominent of which is Victoza (liraglutide, lilalutide), which has reached the level of blockbuster sales.
Lilly's once-a-week hypodermic injection, dulaglutide, was also approved in the US and Europe last year.

At present, peptide drugs for therapeutic purposes are mainly aimed at metabolic diseases and oncology. The former is mainly due to the epidemiological growth of obesity and type 2 diabetes, while the latter needs chemotherapy replacement and cancer support treatment due to the increase of mortality. In North America, peptide therapy occupies the largest market share in the field of diabetes and obesity, and the Asian market is expected to see rapid growth in the future.

In addition, peptide drugs have also been extended to orphan drugs. For example, it has been approved by FDA to be listed in the market, including the GLP-2 receptor agonist teduglutide for the treatment of short bowel syndrome; the somatostatin receptor agonist pasireotide for the treatment of Cushing's syndrome. The current trend also points to the field of infectious diseases and inflammation, in which several peptides are in clinical trials.

At present, about 75% of peptide drugs are administered by injection. However, with the development of technology, more and more attention has been paid to other forms of drug delivery, including oral, intranasal and percutaneous delivery. An example of an alternative route of administration is through the use of gold nanoparticles (midatech) and pharmfilm tongue coating agent technology (monosol

Rx) for oral delivery, midasol

Therapeutics is currently using insulin glycosylated gold nanoparticles for clinical development of oral delivery systems. Another example is actogenix's topact technology platform, which delivers peptides directly to the gastrointestinal tract.

Alternative forms of administration also make peptide therapeutics more widely used in other disease areas. For example, local administration of peptides can be a highly effective new treatment for inflammation.
In addition, peptides are usually good biomarkers, so they can also be used for diagnostic purposes; peptides have also been found to be useful as vaccines.

New peptide technology

Multifunctional peptides have made great progress in the field of metabolism (especially GLP-1 agonists); cell penetrating peptide technology has good targeting, but some of the peptides that are naturally present in the face of the challenge of bioavailability loss are representative and excellent therapeutic agents. In the field of metabolism, such as intestinal tract, microorganisms are rich in diverse bacteria, which can recognize new peptides produced from protein fragments, degradation products or signal molecules. We are convinced that the deepening of microbial research will bring rich opportunities for peptide therapy of metabolic diseases.

However, for innovative peptide drug development, chemists must go beyond traditional peptide technology. Among them, the multi-functional peptide representing a variety of pharmacological activities is a new technology in this field, such as double or even triple excitatory effect. This method needs to be based on genomic information. It is obvious that in knockout animals, only one single gene is knockout, often without obvious phenotype. In addition, although the field of G protein coupled receptor (GPCR) has successfully recognized several selective agonists and antagonists into clinical development, only a few corresponding ligands have finally been approved. However, drug development offers biosystems and multi-target programmes. On the other hand, it is also possible to implement more personalized treatment for patient groups.

Multifunctional peptides currently under development include antimicrobial peptide candidates with additional biological functions, such as immune stimulation and wound healing.

Multifunctional peptides have been better demonstrated in the field of GLP-1 agonists. Several products in the field have been approved for marketing and have achieved great commercial success, including Byetta, bydureon, Victoza, lyxumia and recently tanzeum. Looking at the clinical and preclinical pipeline of new drug development, it is clear that several companies are focused on the development of GLP-1 double or triple agonists for more diversified and personalized treatment of type 2 diabetes and / or obesity (Table 1).

In addition to multi-functional peptides, there is also a focus on improving the convenience and compliance of patients. Therefore, clinical development is also under way for less frequent administration or oral administration of GLP.

Other peptide compounds or molecules with GLP-1 activation include glucagon (GCG), Glucose dependent insulin stimulating peptide (GIP), enterotrypsin B (CCKB) and glucagon like peptide 2 (GLP-2).

The most advanced multifunctional peptide is glp-1-gip and glp-1-gcg double agonist, which is currently in the clinical proof of concept research for overweight and diabetes patients. Glp-1-gcg double agonists, some of which are regulated by natural double acting intestinal peptide prolactin, are expected to provide greater weight loss than GLP-1 agonists in overweight patients with diabetes. Another example is glp-1-cckb double agonist, in which CCKB stimulation plus GLP-1 is expected to enhance the function of pancreatic β cells, which in turn may minimize or prevent the progression of type 2 diabetes. These innovations increase the established effect of GLP-1, and the second activity may increase more effect, so they are suitable for personalized medical solutions.
In recent years, with the development of technology, membrane permeable element implants have appeared, including "cell penetrating peptide", such as membrane penetrating or transcribed trans activator (TAT) sequence, which may reach the intracellular target of peptide to some extent. One of the challenges of cell penetrating peptides is that only a small part of the bioavailable peptides usually reach the target through oral administration, resulting in a great loss of efficacy. Another important aspect is to consider whether the molecular properties of cell penetrating peptides are similar to those of small molecules, including low specificity, which may cause greater security risks due to the increase of distribution volume.

It is worth mentioning that peptide and small molecule, oligoribonucleotide or antibody form conjugates as a new means to develop innovative peptide therapy drugs, which has the effect of improving efficacy and safety. For example, in the field of oncology, this method has gained interest in the industry, more than 20 peptide conjugates in clinical trials.

epilogue

In recent years, polypeptides as therapeutic drugs have attracted more and more attention. More than 60 peptide drugs have been approved for marketing, benefiting patients, and hundreds of new therapeutic peptides are in preclinical and clinical development. This is the key to the success of peptide drug development.

The development of peptide drugs in the future will continue to build on the advantages of natural peptides and improve their weaknesses, such as chemical and physical properties. New peptide technologies, including multifunctional peptides, cell penetrating peptides and peptide drug conjugates, will help to expand the applicability of peptide therapy.

Taking all of the above into account, we are convinced that peptides have great potential as future therapeutic therapies for unmet medical needs.

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About Shengnuo

Chengdu Shengnuo Biotechnology Co., Ltd. has "Chengdu polypeptide drug engineering technology research center" in Chengdu, mainly engaged in polypeptide, polypeptide drug and beauty peptide research. Our zero defect has passed the FDA certification, and now it has become the first-class professional peptide drug and product development, technology transfer, technical service and peptide drug industry in the scale production and export of China's parks.