Peptides in pharmaceutical development have traveled a rough road. It took a long time for these small proteins to emerge as a basis for new medical products. This has become possible mainly because of a convergence of advanced technologies. Meanwhile many drug projects based on peptides are in the pipeline, and several companies offer customized peptides for different applications. Biotech and pharma companies can choose among them like in a supermarket. Here’s a look at the current possibilities and late advances of these little proteins in industry and medicine.

For a long time peptides have remained outside the focus of the pharmaceutical industry. But this has changed. Today peptides are gaining speed as important elements in the research and development of new drugs. The number of new chemical entities based on peptides is rising continuously. While in the 1980s only four to five new chemical entities based on peptides entered clinical studies per year, it was 17 per year from 2010 to 2015. Several factors came together to make this possible. One reason is that scientific, technological and engineering development has improved significantly in recent years. Furthermore the continuous trend to cost efficiency supported the rise of peptides. The small proteins helped bring down the costs of pharmaceutical manufacturing.

It’s the structure and their function that make peptides so interesting for pharmaceutical researchers. Peptides are amino acid polymers. They generally represent a small portion of a full protein and don’t have sufficient activity on their own. But they may be signaling molecules that function through interaction with specific receptors.

The German company Peptides & Elephants states: “Synthetic peptides are able to influence a wide variety of biochemical, immunological and cellular reactions. They may act as inhibitors of protein-protein interactions, interfere with antibody binding to antigens, and they may be substrates or inhibitors of proteases. Likewise, peptides are suited to mimic protein domains and to simulate protein functions.”

Manifold Applications

No wonder peptides today are used in manifold applications, mainly in the areas of oncology, endocrinology, genitourinary medicine, gastroenterology, the central nervous system and immunology. As a result many companies have specialized in developing peptide libraries, firms such as Amyndas, Encycle Therapeutics, Peptidream, Polyphor or the Swiss Bachem. They offer peptides of different size, structure and function in small and huge amounts.

Customers from the pharmaceutical, biotech and also chemical industries can choose individual peptides as if they were buying the ingredients for a cake. In the end they hope to get new lead drug compounds. Experts estimate that the sheer number of companies in the field and the licensing deals they make with large pharmaceutical companies could lead to a further surge of clinical candidates and ultimately of new peptide drugs.

Therefore specialists have a strong look on the latest advances in research findings in which custom synthesized peptides play a key role in advancing science, medicine and technology. The magazine Science Translational Medicine, for example, reports that amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. The magazine Nature Materials describes the synthesis and application of an elastic, wearable crosslinked polymer layer that mimics the properties of normal, youthful skin. It shall be able to improve skin’s elasticity and to eliminate wrinkles. And Nature writes that optogenetics restores the memory in Alzheimer's mouse models. The authors showed that in transgenic mouse models of early Alzheimer’s disease, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval.

Improvement Of Properties

Swiss Bachem, which describes itself as a specialist in the process development and the manufacturing of peptides as active pharmaceutical ingredients (APIs), highlights its cooperation with Japanese GlyTech, a company that makes glycans. The partnership is focused on the chemical development and manufacturing of glycosylated peptides. Glycosylation can improve the physicochemical properties of peptides: solubility, stability, half-life and homogeneity. As a result, this can have positive effects on pharmacological properties of a lead candidate such as better binding, modified receptor selectivity, targeting a specific tissue or organ, and better tolerance.

One goal of the Swiss-Japanese partnership is to improve physicochemical properties of peptides through selective glycosylation. Both chemical structure and position of glycosyl moieties can markedly improve the biological activity of a peptide. While Bachem brings into the cooperations its expertise to scale up and manufacture kilogram scale peptides, GlyTech is capable of producing glycans in kilogram amounts by a proprietary technology.

In 2013, both companies announced that they had successfully co-developed a chemical synthesis of Interferon β-1a applicable on an industrial scale. Interferon β-1a is a 166 amino-acid-long glycosylated protein and an approved drug substance to treat multiple sclerosis with a world market of more than $4 billion.

New Ways Of Delivery

Bachem is also working on new ways of delivery of peptide active ingredients into the human body. The basis for this is a robotic pill that would be swallowed by the patient. The tiny robotic device brings the active ingredient directly to the place in the body where it is needed. There a gas pushes needles into the intestinal wall and discharges the peptide active ingredients.

Another question for scientists is how to get peptides through a cell. Professor Scott Lokey from the University of California-Santa Cruz approaches this topic inspired by natural products and passive membrane permeability. His laboratory studies membrane permeability in molecules whose structures violate classical predictors of “drug-likeness” based on molecular weight and polarity. Many of these “rule breakers” are natural products such as cyclic peptides. Lokey’s mission is to create a drug discovery paradigm that lies at the interface between conventional small molecules and biologics.

A related question concerns professor Roland Brock from Radboud University, Nijmegen Medical Centre. He wants to know how to bring molecules to the cell and detected milk as a blueprint of his peptide-research. Looking at the many ways of uptake of peptides he came to a human lactoferrin-derived peptide as an example. Brock and his team tried to use this method for kidney-specific therapies as there is an urgent need for such treatments.

The Oral Route

The question of oral peptide delivery is in the center of interest for Dr. Leila Hassani-Beniddir, scientist in the Novel Drug Delivery Technologies Group of Ipsen. Mainly because of their poor stability and short plasma half-life, peptides are usually administered by injection, often several times daily. However, the pain and invasiveness of injections, as well as disposal issues associated with used needles and relatively complicated administration protocols mean that alternative routes of delivery are highly desirable for peptides.

Out of all of the available routes of administration, the oral route is the most preferred for its convenience, patient friendliness and cost. However oral peptide delivery faces many hurdles, such as poor absorption, poor permeability and rapid enzymatic or pH-induced degradation in the gastrointestinal tract. The main aim therefore is to improve the absorption. This has been done successfully in mice, Hassani-Beniddir said. She predicted that the oral application of peptides will increase in the next five to 10 years.

There are also researchers focusing on real and practical applications of peptide technology. One is Dr. Don Wellings, CEO of the British company SpheriTech. His company designed several peptides for antimicrobial wound dressing. His aim is to use these products in regenerative medicine for skin repair, stem cell isolation, central nervous system repair, diabetic foot, severe burns or in case of severe accidents.

Looking into the future, peptide experts predict that the evolution of the numerous disciplines involved harbors great promise for peptides. Partnerships and alliances between pioneers in the field of peptides should unleash more productivity increases and catalyze medical progress at affordable rates. Furthermore new peptide drugs and old drugs in new delivery systems are likely to emerge in larger numbers in the decades to come.