New discoveries in peptide-based medicines

New discoveries in peptide-based medicines

As the peptide-based medicines market grows, SciTech Europa highlights some of the recent research to have emerged from the field.

Peptide-based medicines are big business: according to US-based market research and consulting company Grand View Research, the global peptide therapeutic market is expected to reach $48bn (~€42bn) by 2025, spurred on by an increased demand for ‘efficient and rapid-acting therapeutics for treatment of cancer and other lifestyle-associated disorders’.1 it is thus no surprise that a wealth of research is going on in this exciting and evolving area of study.

Engineering oral peptide-based medicines

In a recent breakthrough for peptide-based medicines, researchers at the Technical University of Munich (TUM), Germany, have demonstrated how peptides can be designed for oral administration as a liquid or tablet – a discovery which has previously been hailed as the ‘holy grail of peptide chemistry’.2

Because there are numerous enzymes in the stomach and intestines that break peptide bonds – which link together the short amino acid chains that make up peptides – peptide compounds must be appropriately modified in order to successfully make it through the gastrointestinal tract. A further challenge awaits those that do: the cells of the intestinal walls prevent them from being absorbed into the blood. As such, peptide-based medicines are typically administered as an injectable.

To get around this, the team at TUM used a ring-shaped model peptide comprising six molecules of alanine, a non-essential amino acid, to investigate the effect on oral availability of replacing hydrogen atoms of the peptide bonds with methyl groups.

This resulted in more than 50 variations. Cellular tests performed by collaborators in Israel revealed that only specific peptide variants are absorbed very quickly.

According to Horst Kessler, Carl von Linde professor at the TUM Institute for Advanced Study: “It appears that cyclic hexapeptides with a specific structure are able to use an existing transport system.”

The researchers then selected integrin receptors which control a range of functions on the cell surface as a target for their peptides. Key to the docking at these receptors is a sequence of three amino acids (arginine, glycine and aspartic acid) which the team incorporated at different positions of the model peptide, thereby creating new variants.
The results were mixed. According to TUM, the negatively charged side chain of aspartic acid and the positively charged arginine were both shown to be ‘knock-out criteria’ for using the transport system; however, the researchers were able to mask the charged groups of both amino acids with protecting groups.

As a result of this, the peptide does at first lose its ability to bind to the target molecule, but if the right protective groups are chosen, they are split off again by enzymes in the blood, thus restoring the pharmaceutical effect once they arrive at their destination.

The ‘holy grail of peptide chemistry’

The biological effect of the new hexapeptide has been confirmed in cell tests, where it has been shown to stimulate the growth of blood vessels in low doses. Researchers at Queen Mary University of London, UK, have demonstrated that feeding the masked hexapeptide to mice has the same effect as injecting them with the unmasked hexapeptide.

“In the past, experts have designated the oral availability of peptide-based medications as the ‘holy grail of peptide chemistry’. Our work provides a strategy for solving the challenges of stability, absorption in the body and biological effectiveness,” Kessler explains. “In the future, this will greatly simplify the creation of peptide medication that can be easily given in fluid or tablet form.”

Antimicrobial peptides and antibiotics

Elsewhere, research from Massachusetts Institute of Technology (MIT), USA, has suggested that peptides could play a key role in the fight against antimicrobial resistance, one of the greatest health challenges of the 21st Century.3

Working with scientists from Yale University and local biotech company Visterra, the MIT team were able to significantly enhance the effectiveness of the antibiotic vancomycin against two strains of drug-resistant bacteria by chemically linking it to an antimicrobial peptide.

“Typically, a lot of steps would be needed to get vancomycin in a form that would allow you to attach it to something else, but we don’t have to do anything to the drug,” explains Professor Brad Pentelute, the study’s senior author. “We just mix them together and we get a conjugation reaction.”

According to the researchers, the modification can be easily performed and could potentially be used to create other combinations of antibiotics and peptides. The same approach could even be used to modify cancer drugs.

Linking peptides with small-molecule drugs

The researchers arrived at this discovery after former MIT postdoc Daniel Cohen, one of the study’s lead authors, found that the amino acid selenocysteine is able to spontaneously react with complex natural compounds without the need for a metal catalyst, and that mixing electron-deficient selenocysteine with vancomycin causes it to attach itself to an electron-rich ring of carbon atoms within the antibiotic molecule.

This inspired the researchers to explore the use of selenocysteine as a ‘handle’ for linking peptides and small-molecule drugs. After incorporating selenocysteine into naturally occurring antimicrobial peptides, they discovered not just that the peptides were able to link up with vancomycin but also that the chemical bonds consistently occurred in the same place; all of the resultant molecules were as such identical.

“These complex molecules intrinsically possess regions that can be harnessed to conjugate to our protein, if the protein possesses the selenocysteine handle that we developed,” says MIT postdoc Chi Zhang, another of the study’s lead authors.

“It can greatly simplify the process.”

The researchers tested conjugates of vancomycin and a number of antimicrobial peptides, including dermaseptin, which was shown to be five times more powerful than vancomycin alone against Enterococcus faecalis, and RP-1, which was able to kill Acinetobacter baumannii, despite the antibiotic having no effect on this bacterium by itself.

The team is now working to adapt the method for use with larger proteins and is exploring the possibility of performing the same type of conjugation reaction using cysteine, a more common amino acid, as a handle.

The above examples represent just a snapshot of the exciting work taking place on peptides and their therapeutic application and go some way to explaining why the market for peptide-based medicines will no doubt continue to thrive long into the future.


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