Can We Trick a Parasite Without Tricking Our Own Body?

Imagine designing a drug to attack a parasite, only to realize that the parasite has a protein that looks a lot like one in your own body.

Now you have a problem.

The parasite I looked at, Schistosoma mansoni, has its own version of a protein called acetylcholinesterase, or AChE. Humans have AChE too. So if AChE is going to be targeted, how do you make sure you're targeting the parasite and not yourself?

That was the question I wanted to investigate.

Same Protein, Not Quite the Same

AChE is an enzyme involved in communication between nerve cells and muscles in humans. The parasite has its own version of the enzyme, which has also been studied as a possible drug target.

So I started by comparing the two.

Proteins are made up of smaller building blocks called amino acids. When I compared the amino acid sequences of human AChE and S. mansoni AChE, only 35.4% of the sequence matched.

That was interesting, but I didn't want to stop at a string of letters.

A protein's sequence affects how it folds, and its 3D shape affects how other molecules can interact with it. So I wanted to see whether the differences in sequence also showed up in the structure.

A Doorway You Can't See

This is where things get a little weird, in a good way.

Imagine a building with an important room hidden inside. To get there, you have to go through a doorway.

An enzyme's active site works somewhat like that. It is the part of the protein where molecules interact with it, so the shape around it matters.

I used sequence alignment, protein modeling, and PyMOL, a program for viewing molecular structures, to compare the human and parasite versions of AChE.

In my models, the opening leading toward the active site measured about 9.2 Å in the parasite model, compared with about 4.5 Å in the human structure.

An angstrom, or Å, is an incredibly small unit used to measure things at the scale of atoms and molecules. So no, we're not talking about a doorway you could actually see.

But at this scale, the difference is pretty noticeable.

The two enzymes may do similar things, but their molecular doorways aren't shaped exactly the same.

And that made me wonder: could a drug be designed to take advantage of that difference?

So Could We Actually Target the Parasite?

Not yet.

My research was done using computer-based models, so it doesn't prove that a real drug would behave exactly the way the model suggests. The parasite structure I used was also predicted rather than experimentally determined.

But that's not really the point.

The point is that these differences give researchers somewhere to look.

If a molecule could interact with a structural feature that is different in the parasite's AChE, researchers could potentially investigate whether that difference could be used to design a more selective treatment.

Instead of simply asking, "How do we block this enzyme?" we can ask a more specific question:

"How do we block the parasite's version while avoiding ours?"

That changes what we're looking for.

Why Does This Matter?

Schistosomiasis is a disease caused by parasitic worms and affects millions of people worldwide. Developing treatments that can target the parasite while minimizing unwanted effects on humans is an important challenge.

What I found especially interesting is that this kind of investigation can start without physically having the parasite in front of you.

I used biological data, sequence comparisons, 3D protein models, and molecular visualization to look for differences that would otherwise be difficult to see.

That is what makes computational biology so interesting to me. A protein can look like nothing more than a sequence of letters on a screen, but those letters help determine a complicated 3D structure. A difference that looks tiny in the sequence can give researchers a completely different structure to investigate.

The Tiny Difference

My research did not create a new drug, and it doesn't prove that the parasite's enzyme can be safely targeted.

But it showed me something I hadn't really thought about before.

When two organisms have proteins that perform similar jobs, that doesn't mean the proteins are exactly the same.

Sometimes, the difference is hiding somewhere incredibly small.

In this case, it could be a molecular doorway that's only a few angstroms wide.

And when you're trying to tell a parasite apart from its human host, a tiny difference might be exactly where you should start looking.

Original research paper: Targeting Evolutionary Sequence Divergence in Parasitic Acetylcholinesterase to Treat Tropical Diseases Safely — Namuun Altanshagai