Last updated January 31, 2018 at 4:58 pm
In the second part of the series on antibiotic resistance and the fight to defeat it, we discuss the use of proteins and peptides in drug development.
If you’re looking for the difference between peptides and proteins, the short answer is ‘size’.
Both peptides and proteins are made up of strings of the body’s basic building blocks – amino acids – and held together by peptide bonds. In basic terms, the difference is that peptides are made up of smaller chains of amino acids than proteins.
But the definition, and the way scientists use each term, is a little loose. As a general rule, a peptide contains two or more amino acids. And just to make it a little more complicated, you will often hear scientists refer to polypeptides – a chain of 10 or more amino acids.
Dr Mark Blaskovich from the Institute for Molecular Bioscience (IMB) at The University of Queensland in Australia says approximately 50-100 amino acids is the cut-off between a peptide and a protein. But most peptides found in the human body are much shorter than that – chains of around 20 amino acids.
There’s also an important variant of peptide called the cyclotide. As with the peptide and the protein, the cyclotide is also comprised of a string of amino acids, but unlike the others, the ends of a cyclotide are joined together to form a circle.
As we’ll discuss below, this structure is important in the manufacture of therapeutic peptide-based drugs.
As for proteins, biochemists generally reserve the term for large peptide molecules, which can either be one long chain of 100 or more amino acids – a ‘complex polypeptide’, if you like – or they can be comprised of several amino acid chains joined together.
Haemoglobin, found in your red blood cells and essential for carrying oxygen, is such a protein. It’s made up of four different amino acid chains – two with 141 amino acids each and two with 146 amino acids each.
Why peptides are the ‘next big thing’ in medical research
Biochemists are excited by the possibilities presented by peptides and proteins as pharmaceuticals because they so often mimic exactly the behaviour of a natural ligand – the substance that interacts with the receptor on an enzyme or cell to cause a biological process.
This gives peptide drugs the potential to be more precisely targeted, with fewer side effects than small-molecule drugs.
Within the body, there are lot of different hormones that react with cells and trigger different biological processes. Often these are peptides, either cyclic versions or straight, linear ones.
And then there’s the matter of how fast that peptide breaks down, which causes some stability issues, but in terms of safety, can be a positive.
“We think peptides are the future of drugs for reasons of being more selective, more potent and potentially safer, because when a peptide eventually breaks down it just breaks down into amino acids, and amino acids are food, basically,” says Professor David Craik, who leads IMB’s Clive and Vera Ramaciotti Facility for Producing Pharmaceuticals in Plants.
There are also manufacturing considerations that make peptides attractive – their length allows them to be chemically synthesised, as opposed to proteins that are generally expressed in yeast or mammalian cells.
So that’s peptides. What are the applications for proteins?
The most promising application of proteins is as antibodies, which are themselves a form of protein.
Particularly in anti-cancer applications, there are a lot of antibodies either in the clinic or under development. Two well-known examples are Herceptin (trastuzumab) for breast cancer, and Humira (adalimumab) for rheumatoid arthritis and other autoimmune diseases.
The advantage of using proteins is the same as for the drug applications of peptides – they mimic something that is natural in the body, or replace something that’s missing or damaged.
In the case of antibodies, protein-based drugs use the same strategy as the body does to target things. That way the drug can provide the specificity required, while also avoiding the off-target effects that a small molecule drug can have, causing bad side effects.
When will we see new peptide-based medications?
Stability can be an issue, as peptides can degrade very quickly, and that means it can be difficult to dose a patient with a peptide.
And according to your body, peptides and proteins are basically just food, which makes administering peptide drugs in an oral form quite difficult, as the body promptly digests them.
“That’s why drug developers often try going from a peptide and mimicking it with a small molecule instead, because the small molecule potentially has better properties for a drug, where the small molecule stay around in the body longer and can be administered orally,” Dr Blaskovich said.
But the challenge is to get the small molecule to mimic the peptide.
“Billions are spent by the pharmaceutical industry trying to do this,” Dr Blaskovich added. “That’s why if you’re able to come up with drugs that are peptides, rather than having to convert them into small non-peptidic molecules, it’s potentially a much faster way to develop a potent, selective, and apt drug.”
The pharmaceutical industry remains sceptical, mainly due to the stability issue, but also the difficulty in getting orally administered peptides to cross the barrier of the gut and be taken up by the bloodstream.
But intravenous and subcutaneous use of peptides as drugs is becoming more common. There are around 60 FDA-approved peptide drugs on the market, with about 140 peptide drugs in clinical trials, and over 500 in pre-clinical (before human testing) development.
There are agricultural applications too
While the stability of peptides is a challenge to be overcome in human use, it’s a double-edged sword, and may be an advantage in some agricultural uses. The speed of degradation of peptides used as insecticides or fungicides means that they are not going to persist in the environment.
So creating greater stability of peptides can work both ways.
If the stability of the peptide can be tailored, then it can be made to last long enough to work on the crop, but then also to degrade.
This means it would not cause the long-term problems of DDT, for example, which can exist for hundreds of years.
Why are experts so excited about peptide drugs?
Cyclotides – the central focus of Craik’s work – have great potential to address the issues of stability of peptide drugs.
As they structurally form a circle, cyclotides do not have the weak point of loose ends that speed up degradation by our digestive enzymes. They are further stabilised by several interlocking cross-links, forming a compact, very stable structure. This helps them reach their target intact, even when taken orally.
Blaskovich’s group is working on two promising peptide-based antibiotics to deal with growing antibiotic resistance.
The first of these is to enhance the glycopeptide (peptides with sugar molecules on them) antibiotic Vancomycin, by trying to make it a super-vancomycin that more selectively targets bacterial cells. This approach starts with vancomycin as the core, with additional groups added on to interact selectively with the bacterial cell instead of a mammalian cell.
The aim is to increase its potency at killing bacteria and reduce the unwanted side effects it has on human cells.
The second research program is developing antibiotics that attack Gram negative bacteria – generally considered the more difficult to fight. These peptides are cyclic lipopeptides (peptides with a fatty acid, or lipid, attached) with eight to 10 amino acids.
You might have already taken a peptide-based drug
One of the best-known peptide-based drugs is exenatide, which is marketed under the name Byetta. It’s used to help control blood sugar levels in type 2 diabetes patients.
It works by increasing the insulin production in response to meals and is a synthetic form of the peptide found in the saliva of the Gila monster – a species of venomous lizard native to the US and Mexico.
It’s a linear peptide containing 39 amino acids that was developed some 10 years ago, and is now widely used.
Previous coverage here: Explainer: What is a superbug?