Picture a drug. What comes to mind?
Maybe a round pill, like those we see sold by the hundreds in a single ibuprofen bottle. Or maybe you imagined something more illicit, such as a neat, white, powdery line, scraped into order with a credit card. Or maybe you thought of that needle piercing your shoulder, ready to supply you with a syringe full of a COVID-19 vaccine.
But beyond the pill, the powder, or the syringe, what is a drug, really? What’s in that pill that helps relieve your pain? What gives you immunity to COVID-19? How does it work? Or perhaps, how does it fight its disease-causing opponent?
Drug Duels: Small Molecules vs. Biologics
Just like in wrestling, a drug’s size influences its strategy of attack against its foe or ailment. Most drugs fall into two size categories: small molecule drugs and large molecule drugs, often called “biologics”.
First up, we have small molecules. Weighing in at almost nothing, small molecules are—as their name suggests—quite small, consisting of no more than 100 atoms. But they make excellent use of their size by sneaking past cellular defenses, travelling far and wide in the body.
On the other end of the spectrum, we have biologics. Biologics are large and in charge, coming in at 100-200 times the size of small molecules. They’ve got deadly accuracy and a super strong grip—once they get ahold of their target, they won’t let go.
Small Molecules Sneak Attack
The size difference between small molecules and biologics affects the kinds of opponents they can defeat, or the ailments they can treat.
Because small molecules are tiny, they are stealthier than biologics, allowing them to sneak into our cells. They silently reach their opponent through the gold standard of drug delivery—by mouth—causing minimal discomfort to the patient and enabling an ambush attack on their opponent.
Consider ibuprofen, for example, one of the most well-known small molecule wrestlers around. When in the ring against pain and inflammation, ibuprofen sneaks through our cell membranes to take down a key perpetrator of pain perception, a protein called COX-2.
It might seem like ibuprofen knows where the pain in your body is, targeting in on it with precision. But that’s just a showy trick for the fans: ibuprofen inhibits COX-2 in cells all over your body—you just feel relief in places where pain is present.
A Precise Problem
This brings us to one of the main challenges of small molecule wrestlers: specificity. Small molecules are great at sneaking through cell membranes and going after “intra-cellular” or “inside-the-cell” targets like COX-2, but struggle with only targeting the cells they need to.
This may be fine for a painkiller like ibuprofen, but it poses many more risks for lethal small molecules, the ones that are designed cause cell death.
Take antibiotics, another well-known group of small molecule drugs. Because most antibiotics are broad spectrum bacterial killers, excessive antibiotic use could also kill the good bacteria in your gut that you need for a healthy digestive system.
Or look at chemotherapies, some of the most toxic small molecule drugs available. Chemotherapy drugs are designed to kill cells. This includes cancer cells, but it also includes many normal, healthy cells. Because these drugs lack specificity, chemotherapy has brutal side effects, including hair loss, fatigue, easy bruising and bleeding, low blood cell counts—the list goes on.
Most of the time in drug discovery, we try to develop medicines that either:
- inhibit proteins in our body that are misbehaving (as is the case in many cancers),
- inhibit proteins involved in a response pathway we don’t want (e.g., pain), or
- supply chemicals or proteins our body needs but doesn’t have (e.g., ant-depressants, insulin).
When going up against the first two types of opponents, most small molecules use a “key” and “lock” approach; they act as “keys” that fit their opponent’s “lock”. When ibuprofen binds the COX-2 protein, for example, it fits into a pocket or “keyhole” on COX-2 and “locks” it, inhibiting its activity.
But some opponents don’t have any well-defined “keyholes” for small molecules to home in on. They have shallow surfaces, deflecting any attacks small molecules throw at them. For a long time, these opponents were undefeatable (or “undruggable”) because small molecules couldn’t get a good grip on them.
Small molecules: the seasoned veterans
Despite some of their limitations, small molecules have been in the ring the longest and have collectively taken down the most opponents that challenge the human body. They are seasoned veterans with decades of knockouts to show for it.
But in recent decades, other types of wrestlers with vastly different fighting styles have started to show up. And modern drug development is certainly taking notice.
Biologics are Built Different
One of these newcomers is a class of large molecule drugs called biologics. Due to their massive size, biologics are unlike small molecules in almost every way.
To start, forget sneak attacks—biologics make a loud and proud entrance. They’re far too large to enter our cells, making oral delivery unlikely. Instead, they usually enter the ring by injection into either bloodstream or under the skin.
But what biologics lack in stealth, they make up for in strength and precision. Their massive size allows them to trap their opponents in an inescapable grip. If small molecules are “keys” the fit into opponent “locks”, then biologics are furnaces that envelop them entirely.
Remember those undruggable foes small molecules couldn’t defeat? Biologics are starting to take them down.
While biologics can only reach targets that exist outside of cells, they do so with insanely high specificity. If they do reach their opponent, they expertly get them into a headlock, nearly guaranteeing a win.
One of the most successful biologics to date is a treatment for chronic inflammatory diseases—like arthritis—called adalimumab. Adalimumab is an antibody that is trained to recognize a protein called TNF-alpha. TNF-alpha acts as a messenger to relay inflammatory response signals in the body. By taking out TNF-alpha, inflammation subsides as well.
Divas in Demand
So, what’s their main drawback? Besides the fact that they can’t enter cells, and thus can’t even reach many potential opponents in the body, biologics can be temperamental. They won’t work if they’re too warm or if they’re dehydrated; to keep biologics happy, they must be in a liquid solution and refrigerated or frozen when stored.
Finally, biologics charge a lot to make an appearance. They’re usually harder to make than small molecules, so pharmaceutical companies tend to charge a pretty penny for biologics use.
For example, adalimumab can cost more than $3,000 for a single dose. Insurance companies usually cover most of that cost, but biologics are still aggressively patent protected by their agents. This makes it difficult for others to learn their specific fighting style and creates little competition to bring down exorbitant pricing.
Does One Weight Class Reign Supreme?
In the battle against disease-causing opponents, will one weight class dominate the other? Will the veteran small molecules yield to bigger biologics?
It’s unlikely. We need both classes to attack the multitude of protein targets in our bodies. Both small molecules and biologics each have unique indispensable strengths that the other doesn’t. There’s more than enough room for both to exist in the drug development space.
Best of Both Worlds
In fact, scientists have started to combine the unique strengths of small molecules and biologics to create new drug types that may have the best of both worlds.
In the treatment of cancer, for example, scientists combined toxic chemotherapy small molecules with biologics to create antibody-drug conjugates. The hyper specific biologic guides the small molecule to a cancer cell, and the lethal small molecule goes in for the kill.
There’s also a third size class that occupies the space in between small molecules and biologics, looking to merge the strengths between them. This size class, made mostly of peptide therapeutics, shows promise in having both the sneakiness of small molecules, passing through cell membranes, while also having the specificity of biologics.
Surely, if we can get both small molecule and biologics in the ring together, they may just be unstoppable.
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