Molecular Prosthetics: Small Molecules Replace Missing Proteins
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Molecular Prosthetics: Small Molecules Replace Missing Proteins


Hi, my name is Marty Burke, I am a professor
of chemistry at the University of Illinois and a member of the Carle Illinois College
of Medicine. So molecular prosthetics is the idea that
we can use small molecules to do the job of a missing protein thereby treating diseases
caused by protein deficiency. So it’s often possible to treat a disease
that’s caused by too much function using small molecules that bind to proteins and turn them
off. In fact, most of the drugs we use work that
way. But there are many other diseases caused by
too little function and in these cases it can be much more difficult to treat. For example, severe anemias caused by missing
iron transporting proteins, cystic fibrosis is caused by a missing channel in the lungs,
and a variety of different heart diseases are caused by missing enzymes. In many of these cases, traditional drugs
are ineffective, and as a result, unfortunately many of these diseases remain incurable. But if we can develop small molecules that
perform the main function of these missing proteins, they may be able to operate like
prostheses on the molecular scale to restore functions inside the body. We’ve now discovered a small molecule that
can function like a missing iron-transporting protein. Like a prosthetic hand that could restore
substantial function to an amputee, this compound operates like a molecular-scale prosthetic
to restore the function of a missing protein. Here’s how it works: Normally, iron is transported
across the cell membrane through a protein channel. When one of these proteins is missing, the
iron can no longer flow across the corresponding membrane, and the process of making red blood
cells is therefore blocked. Iron atoms build up at the membrane where
the protein channel usually is. We discovered that a small molecule, called
hinokitiol, can wrap around these built-up iron atoms and transport them across these
membranes, thus acting as a replacement for the missing iron transporting protein. So we tested it in mice, rats and zebrafish. And zebrafish are great because you can see
through them. Here’s a healthy zebrafish. You can see the blood inside of it. This zebrafish is missing one of the iron
transport proteins and thus can no longer make hemoglobin. We found that simply adding this molecule
to the fish tank vigorously restores the capacity for the protein-deficient zebrafish fish to
make hemoglobin in their red blood cells. So we also found that the same small molecule
can restore iron flow across human gut epithelia monolayers grown in the lab. We also found that oral delivery of this compound
to mice or rats missing iron transporters can also restore uptake in their gut. So collectively these studies suggest that
small molecules that perform the functions of missing proteins may represent a way to
treat a wide range of human diseases caused by deficient protein function that have remained
incurable despite all advances we’ve seen in modern medicine.

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