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Sep 29, 2022

Pharmacists

Proxidrugs: Fighting Against Pathogenic Proteins

 Fighting Against Pathogenic Proteins

It's thought that malfunctioning or misfolding proteins play a part in contributing to the development of certain diseases. Today's treatments aim to block these proteins in order to do things like stop the growth of cancer cells or reduce the formation of amyloid plaques in the brain for Alzheimer's. 

However, small molecule drugs can target only 20% of these disease-relevant proteins. That means 80% of these proteins are "undruggable" or untouchable by current medications. 

Dr. Aimo Kannt, Head of Research Division Drug Discovery at Fraunhofer ITMP, believes that a new drug class, proximity-inducing drugs (proxidrugs), could be the answer for reaching more of the 80% and developing treatments for cancer, infections, and neurodegenerative diseases

With other scientists, doctors, and institutions from around the world, Dr. Kannt has started the PROXIDRUGS project to research new treatment avenues. 

What are misfolding proteins?

Misfolding proteins refers to proteins that fail to fold into their functional state due to genetic mutations, abnormal protein modifications, oxidative stress, etc. 

It's common for protein misfolding to happen. Healthy cells can eliminate accumulated or damaged proteins through protein quality control (PQC) systems. In aging and unhealthy cells, these proteins can't clear and overwhelm the capacity of the PQC, leading to many debilitating diseases, such as:

How proxidrugs can fight pathogenic proteins

Recent information suggests that proxidrugs can fight disease-relevant proteins in a few ways. 

Destroy the cause of the disease

Most traditional medications, like those prescribed for high blood pressure and inflammation, wear off when the body metabolizes the drug. As a result, they must be taken regularly. 

On the other hand, proxidrugs can cause protein degradation by detecting defective proteins. Once this protein is identified, it's marked by the ubiquitin molecule, a small protein responsible for controlling other proteins in our body. This marker signals protein to the proteasome, which breaks down and destroys unwanted proteins. 

Control the cell's own waste removal system

With the help of an enzyme called E3 ligases, the ubiquitin molecule pinpoints disease-related proteins. The cell's waste removal system (lysosomes) recognizes these proteins as waste, allowing the proteasome to degrade them. 

Researchers say that proxidrugs are built to bind to a disease-relevant target protein, thus completely destroying the pathogenic protein. 

Fight multidrug-resistant germs

Proxidrugs offer the opportunity to fight infectious diseases caused by multidrug-resistant bacteria, germs that have become resistant to multiple antibiotics. 

For example, researchers are studying closely how these drugs may treat Acinetobacter baumannii, a bacteria commonly found in healthcare settings that cause infections in the blood, urinary tract, and lungs (pneumonia) or in wounds. 

Next steps 

In addition to Fraunhofer ITMP, Goethe University Frankfurt, Technical University of Darmstadt, Max Planck Institute of Biophysics, and pharmaceutical companies Merck and Abbvie are part of the ten researchers involved in testing proxidrugs against pathogenic proteins.

Although it may be some time before proxidrugs become a standard treatment for certain diseases and illnesses, clinical trials have already been started worldwide. 

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