Image courtesy of Wikimedia Commons.
Many neurological disorders are linked to the accumulation of harmful proteins in the brain, such as alpha-synuclein proteins in Parkinson’s disease. A promising new tool known as targeted protein degradation (TPD) has emerged as a treatment for these conditions. TPD employs small molecules, called degraders, to destroy pathogenic proteins in the body. Unlike current treatments that only alleviate symptoms, TPD can theoretically address the root cause of the symptoms by removing harmful proteins. However, current TPD treatments are limited because the degraders are unable to cross over to the central nervous system (CNS), which includes the brain and spinal cord. This is because of the blood-brain barrier (BBB)—a uniform layer of cells that lines the inner surfaces of blood vessels in the brain and controls what molecules can enter and exit.
However, a team of Yale chemists, including graduate student Rinco Wang (GSAS ’28), has recently made a breakthrough by designing a family of molecules called transcytosis-inducing molecular degraders of extracellular proteins, or TransMoDEs for short. Transcytosis is the process by which molecules are transported from one side of a cell to the other. The scientists created these molecules by bonding drug molecules to a synthetic peptide called Angiopep-2, which can be transported through the BBB. In this case, the researchers added biotin and chloroalkane, which bind to proteins called streptavidin and HaloTag, respectively. By attaching drugs to a peptide known to cross the BBB, the researchers hypothesized that the drugs could also sneak through the BBB.
To demonstrate TransMoDEs’ capabilities, the researchers examined the behavior of TransMoDEs in an in vitro—meaning outside a living organism—model of the BBB derived from mouse cell cultures. The bacterial protein streptavidin was used as a proof of concept to simulate pathogenic proteins from neurological diseases because streptavidin has a similar molecular weight to many neurotoxins. The results showed that TransMoDEs could transport material to the other side of the BBB and successfully degrade target proteins. Furthermore, contrary to previous assumptions, the researchers found that TransMoDEs could successfully enter the BBB through multiple receptors, not just the low-density lipoprotein receptor-related protein 1 receptor that is typically associated with Angiopep-2. This finding suggests that TransMoDEs employ alternative mechanisms of transport, expanding their utility for targeting different kinds of cells.
This study represents the first successful demonstration of a TPD approach that can cross the BBB, opening the door for potential treatments for neurological diseases. “[TransMoDEs could] deplete the alpha-synuclein toxins to either slow down or disrupt the progress of Parkinson’s disease,” Wang said. Moving forward, the lab is working on optimizing the TransMoDEs so they can eventually be used as a drug to treat diseases like Parkinson’s. First, the scientists want to determine how the Angiopep-2 peptide binds to its receptor in order to optimize the structural designs of TransMoDEs. “When we design this as a drug to treat patients, we want to use as few of the drugs [as possible] to treat the patients and see as high depletion of the neurological toxins,” Wang said. If TransMoDEs prove successful, the pathogenic proteins in the brain that have been shielded by the BBB may no longer be inaccessible.