Discovery of chemical endocytosis could redefine precision medicine
A team of scientists, notably Zhengyu Wang, PhD, assistant professor in the department of pharmacology and the Barshop Institute, led by Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology with the department of pharmacology and the Barshop Institute at The University of Texas Health Science Center at San Antonio (UT Health San Antonio), together with two other teams led by Hui-kuan Lin, PhD, from Duke University (Duke) and Zhiqiang Qin, MD, PhD, from the University of Arkansas for Medical Sciences (UAMS), uncovered the mechanism of cellular uptake for large and polar drugs and devised a novel strategy to optimize the capacity of drug delivery into these cells.
Published online April 17, 2025, in Cell, the study creates a strategy called chemical endocytic medicinal chemistry that may revolutionize how endocytic drugs in the future are designed and developed. Other contributors to this publication include Bo-Syong Pan, PhD, Rajesh Manne, PhD, and Che-Chia Hsu, PhD, (Duke); Jungang Chen, PhD, Phuc Tran, PhD, Tsigereda Weldemichael, PhD, and Jingwei Shao, PhD, (UAMS); and Dongwen Lv, PhD, Minmin Wang, PhD, Wei Yan, PhD, assistant professor, Hongfei Zhou, PhD, Gloria M. Martinez, PhD, Robert Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine and Daohong Zhou, MD, professor, associate director for drug development at the Mays Cancer Center and director of the Center for Innovative Drug Discovery (UT San Antonio).
“Chemical endocytic medicinal chemistry has the potential to impact every aspect of endocytic drugs from drug discovery and development to clinical practice,” said Li.
In this novel process, drug molecules are designed to better engage with CD36, a protein receptor found on the surface of many cells. By optimizing chemical interactions with CD36, the team was able to enhance the natural function of CD36, essentially escalating up the gateway for larger and polar drug compounds to enter the cell.
“This innovative chemical approach can potentially make any intravenous drug able to be taken orally. It can also promote any drug crossing the blood-brain barrier. This will remarkably broaden the number of agents we have to treat brain cancer or dementia,” said Robert A. Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.
Overcoming the ‘Rule of 5’ barrier for drug development
Small-molecule drugs have been limited due to the belief that passive diffusion was the primary mechanism of cell entry. One of the most promising developments in recent years in drug discovery is induced proximity. This drug discovery process utilizes molecules to bring proteins together to create a desired protein interaction and/or chemical reaction. Until now, molecules larger than 500 Daltons (Da) were believed to be practically unusable due to the challenges of cell access and bioavailability. This greatly restricted the kinds of compounds that could be developed as induced proximity drugs.
This new mechanistic discovery bypasses this limitation by chemically enhancing CD36-mediated uptake, amplifying the efficiency of larger and polar molecules to enter target cells. CD36 was known to play a role in lipid transport and metabolism, but the team found it also had unexpected potential for promoting cellular uptake of large and polar chemical drugs.
“This discovery is important because it could rescue many drugs that were previously considered unusable due to poor absorption and turn them into clinically useful treatments for diseases,” said study author Hui-Kuan Lin, PhD, a cancer biology researcher and professor in the Department of Pathology at Duke University School of Medicine.
Provocative but well-validated results
In the study, the team first discovered and validated the CD36-mediated endocytic uptake of large and polar chemical compounds with sizes between 543 and 2,145 Da and then tested the efficacy of optimized CD36 action on the cellular uptake of proteolysis targeting chimeras (PROTACs), a class of large molecular compounds that includes an E3 ligase protein-binding domain, a binding domain for a target protein, and a linker. The team was astonished at the speed, effective uptake and potency of the compounds when utilizing the chemical endocytic medicinal chemistry strategy through CD36 interaction.
“This was completely unexpected in the research field,” said Li. “For decades, it was thought that molecules this large couldn’t cross membranes effectively, since the endocytic cellular uptake of chemicals was unknown. Through chemistry and biology, we identified CD36 as a protein for uptake and optimized chemicals better engaging with CD36 to internalize these drugs to more efficiently reach target proteins,” said Li.
The key experimental results were independently reproduced by each of the teams involved in the study.
“As the research conclusion is so provocative, we verified the key results multiple times,” said Li. “The implications of this for drug discovery and development are enormous.”
Rewriting the rules: Implications for drug development and the FDA
Traditional drug development is an extensive, expensive process focused on optimizing chemical compounds for passive diffusion into a cell by considering its contradictory characteristics of permeability, solubility and stability. This new process for endocytic drugs represents a paradigm shift that removes these challenges by using the membrane receptor-mediated cellular entry.
“This breakthrough discovery will force us to rethink how we approach efficacy and pharmacokinetics and toxicity,” said Li. “We believe it will also eventually change how regulatory agencies like the [Food and Drug Administration] FDA evaluate and approve new endocytic drugs.”
Patient stratification based on different CD36 expression
By analyzing tissue from prostate cancer patients, the team found CD36 expression levels varied widely. Li said this may explain why different patients respond differently to some cancer medications.
“By optimizing CD36 engagement through chemical endocytic medicinal chemistry, we may be able to target cancer and other diseases precisely through precision treatment based on the differential expression of CD36 in various tissues and different individuals,” said Li.
What comes next
Li said that, along with CD36, it is likely that there are additional cell receptors that could be targeted for chemical endocytosis, which Li’s laboratory continues to explore. He said the field of drug development may be significantly different in the next couple of decades due to this discovery and the potential it brings to induced proximity drugs. Li said there are high levels of CD36 receptors in intestine, brain and skin cells as well, so the chemical endocytosis strategy brings promise for better drug delivery that provides higher oral bioavailability, effectively bridges the blood-brain barrier or enters through the skin.
“In the next 10 to 20 years, this may become a foundational approach in drug discovery and a new research field within medicinal chemistry. We feel incredibly lucky to have made this discovery and opened the door to hope for previously untreatable diseases,” said Li.
C36-mediated endocytosis of proteolysis-targeting chimeras
Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, Jungang Chen, Dongwen Lv, Minmin Wang, Phuc Tran, Tsigereda Weldemichael, Wei Yan, Hongfei Zhou, Gloria M. Martinez, Jingwei Shao, Che-Chia Hsu, Robert Hromas, Daohong Zhou, Zhiqiang Qin, Hui-Kuan Lin, Hong-Yu Li
Cell
First published April 17, 2025.