A NEW TYPE OF MEDICINE, CUSTOM-MADE WITH TINY PROTEINS

01.07.20

WHAT'S IT ABOUT?

Overview from TED

Some common life-saving medicines, such as insulin, are made of proteins so large and fragile that they need to be injected instead of ingested as pills. But a new generation of medicine - made from smaller, more durable proteins known as peptides - is on its way.

Molecular engineer and TED Fellow Christopher Bahl explains how he's using computational design to create powerful peptides that could one day neutralise the flu, protect against botulism poisoning and even stop cancer cells from growing.

"Creating a new drug is a lot like crafting a key to fit a particular lock... We need to get the shape just right."

White Brick Wall
Christopher Bahl

Molecular Engineer

TED Fellow Christopher Bahl uses computational protein design - building never-before-seen-in-nature proteins with the aid of computers - to develop new medicines for use in combating infectious diseases.

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MY TAKE...

This short yet informative talk from TED Fellow, Christopher Bahl – a molecular engineer – centres on the development of a new type of medicine. Using computational protein design, Bahl and his collaborators have built never-before-seen-in-nature proteins which may one day prove crucial in combating infectious diseases.


Given my day job, I’m endlessly fascinated by discoveries and advancements in the medical field. A custom-made medicine is one such innovation. Bahl analogises:


Creating a new drug is a lot like crafting a key to fit a particular lock. We need to get the shape just right.


Sounds simple, right? Wrong. We’re not talking about adding a few grooves here and there. As Bahl explains:


If we change the shape of a constrained peptide by too much, those extra chemical bonds are unable to form and the whole molecule falls apart. So, we needed to figure out how to gain control over their shape.


The “we” Bahl refers to constituted a collaborative effort that spanned a dozen institutions across three continents. Hardly your local locksmith...


But to truly appreciate the complexity at play here, it is first important to learn what peptides are and how they could bring about a tidal wave of new and exciting medicines.

PEP TALK

Peptides are short chains of amino acids that act as signalling molecules, controlling diverse functions within the human body.


According to Science Daily:


Well-known examples include insulin, which comprises 51 amino acid building blocks and controls the metabolism of sugar, or cyclosporine, an 11 amino acid-peptide that has been proven to suppress organ rejection after transplants.


As of May 2019, there were 60 approved peptide drugs on the market in the US, Europe and Japan, with more than 400 under clinical development. With a handful of peptide medications already commanding billions in revenue, it’s not hard to see that the demand is there. But there has been one major problem – they cannot be administered as tablets.


An article by Jolene L. Lau and Michael K. Dunn in Bioorganic & Medicinal Chemistry outlines this historical issue:


[An] obstacle for peptidic drug development is oral bioavailability: digestive enzymes designed to break down amide bonds of ingested proteins are effective at cleaving the same bonds in peptide hormones, and the high polarity and molecular weight of peptides severely limits intestinal permeability. As oral delivery is often viewed as attractive for supporting patient compliance, the need for injection made peptides a less appealing option for indications that required chronic, outpatient therapy.


In other words, natural enzymes in our stomach and intestines break peptide bonds, meaning drugs based on unmodified peptides have no chance of surviving. As such, they're usually administered by injection. But Bahl and Co. have other ideas…


The beauty of their custom-made “constrained” peptides is that they can be administered as pills. A truly game-changing advancement if it comes to fruition.


Whilst only a few constrained peptide drugs are available today, Bahl anticipates a great deal more will hit the market in the coming decade.


So, how do constrained peptides differ from their unconstrained counterparts? And what could this mean for the future of medicine?

THE FUTURE OF MEDICINE?

Typically, biologic drugs (those made of protein) are large but fragile. Constrained peptides, however, are the opposite. They benefit from extra chemical bonds that constrain the shape of the molecule, making them highly potent yet incredibly stable. They can therefore be administered using pills, inhalers or ointments, making them highly desirable for drug development. Or, as Bahl so aptly puts it:


They combine some of the best features of small-molecule and biologic drugs into one.


It’s not surprising, then, that constrained peptides are receiving such focus. What I found most interesting, however, is the way the team went about their design. Bahl explains:


We took a radically different approach from previous efforts. Instead of making changes to the constrained peptides that we find in nature, we figured out how to build new ones totally from scratch. To help us do this, we developed freely available open-source peptide-design software that anyone can use to do this, too.


He continues:


When we compared our designed models with the real molecular structures, we found that our software can position individual atoms with an accuracy that's at the limit of what's possible to measure. Three years ago, this couldn't be done. But today, we have the ability to create designer peptides with shapes that are custom-tailored for drug development.


The fact that open-source “peptide-design software” exists encapsulates why I love technology. That such a sophisticated programme is available – for free – for anyone to use demonstrates the best of computing and communication.


Whilst I don’t personally have a penchant for poring over proteins (I’m not sure many of us do?), it’s a wonderful example of how knowledge sharing leads to increased awareness, interest and inclusivity. Who knows, their software may be what inspires the next generation of scientists - the brightest brains of the future!


For now, however, patience is the name of the game. It’s estimated that it can take 15 years and $1 billion in development, testing and licensing to bring a drug to market, but Bahl is confident it will be worth the wait:


Constrained peptide design is a cutting-edge technology, and the drug development pipeline is slow and cautious. So, we're still three to five years out from human trials. But during that time, more constrained peptide drugs are going to be entering the drug development pipeline. And ultimately, I believe that designed peptide drugs are going to enable us all to break free from the constraints of our diseases.


That’s quite the statement. Especially seeing as the team claim to have designed constrained peptides that neutralise influenza virus, protect against botulism poisoning and block cancer cells from growing.


Only time will tell if Bahl’s predictions are correct, but we can be certain of one thing now: there’s a lot of promise in those tiny proteins!

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