Major breakthrough could turn IV drugs into oral treatments for brain cancer and Alzheimer’s

A research team led by scientists from the University of Texas Health Science Center in San Antonio (UT Health San Antonio) made a major breakthrough with the potential to convert IV drugs into oral treatments for diseases such as brain cancer and Alzheimer’s disease.

The discovery can reform how medicines are designed, supplied and administered. Currently, complex and great molecul medicines for difficult to treat cancers and other diseases cannot be administered as a pill and easily absorbed in cells, and therefore must be delivered by intravenous or infusion.

But these researchers unveiled a new strategy called chemical endocytic medicinal chemistry that could all change, and even influence how the FDA evaluates future medicines, while helping to adjust treatments based on the unique biology of a patient – who take in a new era of precision and personalized medicine.

This innovative chemical approach can possibly be taken orally every intravenous medicine. It can also promote any medicine that exceeds the blood-brain barrier. This will remarkably broaden the number of drugs that we must treat to treat brain cancer or dementia. “

Robert A. Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine at Ut Health San Antonio

The findings were published on April 17 in the magazine Cellentitled, “C36-mediated endocytosis of proteolysis targeting chimeras.” It was led by Hong-YU Li, PhD, professor of medicinal chemistry and chemical biology at the Department of Pharmacology and SAM and Ann Barshop Institute for Longevity and Aging Studies at Ut Health San Antonio, in collaboration with partners at Duke University and the University of Arkansas.

Their strategy uses the body’s own protein receptors on the surface of many cells called CD36 to help large and water -soluable “polar” medicines to introduce cells more efficiently. They demonstrated how chemical optimization of interactions with CD36 drugs that were previously thought too large to be absorbed by cells.

Li said that chemical endocytic medicinal chemistry – with “endocytic” that describes the process of cells taking substances from their environment – has the potential to influence any aspect of endocytic drugs from discovering medicines and development to clinical practice. “The implications of this for discovering and development of medicines are huge,” he said.

For San Antonio, this discovery reinforces the emerging status of the city as a leader in biomedical innovation, in particular through the work of UT Health San Antonio’s Barshop Institute, May’s Cancer Center and Center for Innovative Drug Discovery.

Overcome barriers for the development of medicines

Medicines with small molecules are limited due to the conviction that the primary mechanism of cell entry was passive diffusion or not actively driven. One of the most promising developments in recent years in discovering medicines is induced proximity, in which molecules bring proteins together to create a desired interaction and/or chemical reaction.

So far, molecules greater than 500 Daltons (DA), which refer to mass units used to measure the molecular weight, are practically unusable because of the challenges of cell access and biological availability. This limited the types of connections that could be developed as induced proximity drugs greatly limited.

The new mechanistic discovery by the Li team bypasses this limitation by chemically improving the recording of CD36-mediated admission, which strengthens the efficiency of larger and polar molecules to enter target cells. It was known that CD36 played a role in lipident transport and metabolism, but the team thought it also had unexpected potential for promoting cellular intake of large and polar chemical medicines.

It could also revive medicines that were previously considered unusable due to poor absorption and they turn into useful treatments.

Provocative but well -validated results

In the study, the team discovered and validated for the first time the CD36-mediated endocytic recording of large and polar chemical connections with sizes between 543 and 2.145 DA and then tested the effectiveness of optimized CD36 operation on the cellular recording of “proteolysis” (Protacs). They refer to a class of large molecular connections that includes an E3-ligase protein-binding domain, or a binding domain for a target protein and a left.

The team was surprised by the speed, effective admission and potential of the connections in the use of the chemical endocytic drug strategy by CD36 interaction.

“This was completely unexpected in the research area,” said Li. “For decades, it was thought that molecules that these large membranes could not effectively cross because the endocytic cellular recording of chemicals was unknown. By chemistry and biology we identified CD36 as a protein for admission and optimized chemicals to be better reduced with CD36” “

The most important experimental results were independently reproduced by each of the teams involved in the research.

“Because the conclusion of the research is so provocative, we have verified the most important results several times,” said Li. “The implications of this for discovering and development of medicines are huge.”

Implications for the development of medicines

Traditional drug development is an extensive, expensive process aimed at optimizing chemical compounds for passive diffusion in a cell by considering the conflicting characteristics of permeability, solubility and stability. This new process for endocytic medicines represents a paradigm shift that removes these challenges by using the membrane receptor-mediated cellular access.

“This breakthrough discovery will force us to reconsider how we approach efficacy and pharmacokinetics and toxicity,” Li said. “We believe that it will ultimately also change how regulatory authorities such as the FDA evaluate and approve new endocytic medicines.”

By analyzing fabric of prostate cancer patients, the team found CD36 expression levels greatly varied. Li said this can explain why different patients respond differently to some cancer drugs.

“By optimizing the involvement of CD36 through chemical endocytic medicinal chemistry, we may be able to focus on cancer and other diseases, precisely through precision treatment based on the differential expression of CD36 in different tissues and various individuals,” he said.

What comes afterwards

Li said that, together with CD36, there is probably additional cell receptors that can be aimed at chemical endocytosis, who continues to investigate Li’s Laboratory. He said that the area of ​​drug development in the coming decades can vary considerably because of this discovery and the potential that it entails for induced proximity medicines.

There are also high levels of CD36 receptors in intestinal, brain and skin cells, he said, so the chemical endocytosis strategy brings promising for better medicine emission that offers a higher oral biological availability, effectively bridges the blood-brain barrier or gets through the skin.

“In the next 10 to 20 years this can be a fundamental approach when discovering medicines and a new research area within medicinal chemistry,” Li said. “We feel incredible happiness that we have made this discovery and opened the door for hope for rather untreatable diseases.”