Novel ‘Chimera’ drug targets the ‘undruggable’ Parkinson’s protein
Inspired by a creature from Greek mythology, researchers have created a ‘two-headed’ drug that prevents the production of the toxic protein linked to Parkinson’s disease before destroying the RNA machinery that makes it. The novel drug may be a way of slowing or even stopping the disease’s progression.
In Greek mythology, the Chimera was a fire-breathing hybrid composed of different animal parts, usually portrayed as a lion with a goat’s head springing from its back and a tail that ends in a snake’s head.
Inspired by this mythical creature, researchers at the Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology (UF Scripps) have created a ‘two-headed’ drug that could effectively treat Parkinson’s disease.
“To change the course of this disease, we need to address its cause,” said Matthew Disney, corresponding author of the study. “For many Parkinson’s patients, that apparent cause is the accumulation of a toxic protein called alpha-synuclein, in and around their neurons.”
Current Parkinson’s medications replace the dopamine that’s depleted as neurons responsible for producing the neurotransmitter are lost due to an accumulation of alpha-synuclein. While the drugs improve the quality of life of people with Parkinson’s, they are only managing the symptoms of the disease; they’re not a cure.
Rather than alleviating symptoms, the researchers wanted their drug to target the toxic alpha-synuclein protein at the heart of Parkinson’s disease. It is not an easy task, as alpha-synuclein has been considered ‘undruggable,’ a challenging drug target due to its unruly, disorganized form and lack of druggable structures.
“In situations like this, we have found that targeting the RNA needed to build the toxic protein may be an optimal strategy to slowing or even stopping disease progression,” Disney said.
Proteins are assembled in the body’s cells through a process that involves the reading and translation of a gene, the transport of that information from the cell’s nucleus to its cytoplasm via messenger RNA (mRNA), and ribosomes, the cellular machinery responsible for making proteins. Each ribosome is made up of two subunits that lock around the mRNA and travel along its length, reading its protein-making ‘instructions’.
The researchers started with Synucleozid-2.0, a drug-like small molecule that binds to a section of alpha-synuclein (SNCA) mRNA that tells the ribosome to start assembling the protein. The drug inhibits alpha-synuclein translation by preventing ribosomes from assembling onto SNCA mRNA (that’s head number one). The RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) that selectively degrades cellular SNCA mRNA (head number two). Hence, the drug’s two-headed – chimeric – effect is realized.
RNA sequencing and proteomics studies demonstrated that the drug, which the researchers have called Syn-RiboTAC, reduced the mRNA’s protein levels and rescued the expression of around 50% of the genes that were abnormally expressed in dopamine-producing neurons derived from Parkinson’s patient-derived induced pluripotent stem cells (iPSCs).
“In Parkinson’s mouse models, we see that reducing alpha-synuclein by even 25% is therapeutically beneficial,” said Yuquan Tong, the study’s lead author. “In studies from induced neurons of Parkinson’s patients, we see the Syn-RiboTAC strategy reduces alpha-synuclein production by about 50%. We saw that adding the RiboTAC produces a significant gain in potency.”
The drug’s selectivity, which is important for avoiding unwanted side effects, and its blood-brain barrier penetration were better than other compounds the researchers studied. They plan to refine their two-headed drug to improve its properties, including developing it into an oral bioactive medicine.
“The medical need for a truly disease-modifying treatment is significant, and we know that patients are awaiting better options,” said Disney. “We’re hopeful that we’re on the road to better days for people living with Parkinson’s.”
The study was published in the journal PNAS.
Source: UF Scripps