Afara designs small molecules to carry a disease-causing protein to the cell’s own recycling machinery, so the protein can be taken apart. Each molecule aims to let go and move on to the next protein.
Thousands of kinds of protein are made, do their work and are broken down again, all day. The cell has its own way to clear the ones it no longer needs.
Proteins from published structures, at true size relative to each other. Behind them, real cells under a fluorescence microscope (ZEISS Microscopy, CC BY 2.0), not to the same scale. The scale bar is measured at the focal plane.
Sometimes a cell makes too much of a protein, or makes it in a faulty form. Many medicines sit in a pocket on that protein to block it. They have to stay there to work, and many proteins have no pocket to sit in.
The problem protein, from a published structure (PDB 5T35).
A degrader molecule has two ends joined by a short link. One end holds the problem protein. The other holds a ligase, an enzyme whose job is to mark proteins for removal. For a moment, the two are held side by side.
The real crystal structure (PDB 5T35) of the degrader MZ1 holding BRD4’s second bromodomain to the VHL ligase complex.
Held this close, the ligase hangs a chain of small proteins called ubiquitin onto the problem protein. To the cell, the chain is an instruction.
Ubiquitin is 76 amino acids long.
The proteasome is a barrel with a cap at one or both ends. The cap reads the tags, pulls the protein in and unfolds it; the barrel cuts it into short pieces the cell can use again.
The human proteasome, from a published cryo-EM structure (PDB 5GJR). The pale background is styling only: the proteasome, under 50 nm long, is far too small for a light microscope to see.
In laboratory studies, a degrader is not used up when the protein is handed on and taken apart in the shredder. It is designed to carry the next one, and the next. Scientists call this a catalytic way of working.
We look for a place on the problem protein where a small molecule can hold on, even briefly. It does not need to block anything. Holding is enough.
People have hundreds of ligases. We choose one that is active in the tissue where the disease is.
The link sets the distance and angle between the two proteins. Small changes decide whether the tag can be placed at all.
In this 3D view: far red, the problem protein; blue, the ligase; green, the bridge molecule.
Each programme is a lane. The further its band has travelled, the further it is in testing. All programmes are investigational and none is approved. Sample data.
| Programme | Area | Target type | Stage | Next milestone |
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Led protein science teams for 15 years before founding Afara.
Fictional personA structural biologist who studies how proteins fit together.
Fictional personA blood cancer doctor who leads our studies in people.
Fictional personFunds the long road from the lab to the clinic.
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