In a landmark breakthrough destined to redefine pharmaceutical science, researchers at The University of Texas Health Science Center at San Antonio have unveiled a pioneering strategy poised to revolutionize the administration of intravenous drugs. Traditionally, many complex therapeutics, particularly those targeting formidable challenges like brain cancer and Alzheimer’s disease, rely solely on intravenous delivery due to their bulky molecular structures and the inability to permeate cellular membranes effectively when administered orally. This new chemical approach, termed chemical endocytic medicinal chemistry, promises to break these longstanding barriers by harnessing the cell’s own protein receptor mechanisms to facilitate efficient drug absorption.
The innovative research centers on the cellular membrane receptor CD36, a protein previously recognized primarily for its role in lipid transport and metabolic pathways. By chemically tailoring drugs to enhance their affinity for CD36, the team demonstrated these larger and polar molecules—historically considered too large for cellular uptake—could be internalized efficiently. This tactic fundamentally overturns the former dogma that compounds over 500 Daltons in molecular weight were incompatible with oral delivery, instead revealing a receptor-mediated pathway that actively imports even sizable drug molecules into cells.
At the forefront of this discovery, Professor Hong-yu Li and colleagues meticulously explored the biological interplay between proteolysis-targeting chimeras (PROTACs) and CD36. PROTACs, a novel class of bifunctional molecules capable of recruiting a target protein to an E3 ubiquitin ligase to induce degradation, have been constrained by their molecular weight and physicochemical properties, which hinder their bioavailability. Li’s team reported that by fine-tuning these compounds’ chemical structures to engage the CD36 receptor, PROTAC uptake was drastically amplified, markedly enhancing cellular penetration and pharmacological efficacy.
This elegant merger of medicinal chemistry and cellular biology reflects a paradigm shift, challenging the pharmaceutical industry’s long-held reliance on passive diffusion as the central mechanism for drug entry. Passive diffusion necessitates an intricate balance between solubility and membrane permeability, often compromising therapeutic optimization. The CD36-mediated endocytosis strategy provides an alternative, active transport route, inviting revisitation of drug candidates previously discarded due to unfavorable absorption profiles and opening avenues for more precise, individualized therapies.
One particularly exciting implication of this research lies in its capacity to enable drugs to traverse the blood-brain barrier — a notoriously selective and protective interface that restricts the passage of most therapeutics. By leveraging CD36 receptors, which are abundantly expressed not only in the intestine but also in brain endothelial cells and the skin, these chemically optimized compounds could achieve improved oral bioavailability and effective central nervous system penetration. This breakthrough suggests new hope for treating neurodegenerative diseases and brain cancers, conditions where therapeutic options are severely limited by delivery challenges.
The methodology employed by Li’s team involved rigorous experimental validation across multiple collaborating institutions, including Duke University and the University of Arkansas for Medical Sciences. Their approach utilized experimental assays to quantify cellular uptake rates of large polar molecules via CD36 engagement, confirming the specificity and efficiency of this pathway. Impressively, these findings were independently reproduced by all participating teams, reinforcing the robustness and credibility of the discovery.
Moreover, the researchers uncovered the variability of CD36 expression in human tissues, particularly within prostate cancer patient samples, which might elucidate differential drug responses seen clinically. This heterogeneity emphasizes the potential of chemical endocytic medicinal chemistry to be adapted into precision medicine frameworks, tailoring treatments based on individual receptor profiles. Such personalized targeting could diminish adverse effects and maximize therapeutic outcomes by directing drugs explicitly to tissues with high CD36 presence.
This groundbreaking work also challenges pharmacokinetics and toxicity paradigms currently embedded in drug development and regulatory evaluation. Since drug candidates designed for passive diffusion are optimized for molecular properties that fit narrow physicochemical windows, the active CD36-mediated uptake may demand new criteria and testing frameworks. Regulatory bodies like the FDA might soon have to recalibrate their assessment strategies to accommodate these innovative endocytic therapies, heralding a fresh chapter in drug approval processes.
Looking forward, Li’s laboratory is actively exploring other membrane receptors beyond CD36 that may similarly facilitate the endocytic uptake of large and polar molecules. This ongoing research could exponentially expand the toolkit for chemically mediated drug delivery, offering the pharmaceutical industry an array of receptor targets to customize therapeutic entry routes. The implications for diseases with previously intractable drug delivery obstacles are profound, potentially transforming clinical practice over the next decades.
The significance of chemical endocytic medicinal chemistry reverberates beyond its molecular intricacies; it signals a robust shift in how drugs might be conceived, optimized, and administered. By moving away from passive diffusion constraints towards receptor-mediated cellular internalization, scientists and clinicians are poised to unlock the therapeutic potential of molecules once deemed unviable. This innovation could not only revive aging drug libraries but also catalyze the emergence of novel therapeutics designed explicitly with such active uptake mechanisms in mind.
In addition to advancing drug discovery, this breakthrough strengthens San Antonio’s burgeoning role as a biomedical innovation hub. Institutions such as the Sam and Ann Barshop Institute for Longevity and Aging Studies, the Mays Cancer Center, and the Center for Innovative Drug Discovery at UT Health San Antonio are at the vanguard of translational research efforts that bridge chemistry, biology, and clinical therapies. Their collaborative environment fosters innovations like chemical endocytic medicinal chemistry, promising tangible improvements in patient care and disease management.
As the molecular weight frontier for drug design expands, the clinical armamentarium is expected to diversify dramatically. Diseases once limited by delivery bottlenecks may soon be tackled using orally bioavailable, endocytic-mediated treatments, propelling precision medicine into new territory. The cross-disciplinary nature of this discovery embodies the future of biomedical research: where chemical ingenuity converges with cellular understanding to solve some of medicine’s most persistent challenges.
The research was published on April 17, 2025, in the journal Cell, under the title “C36-mediated endocytosis of proteolysis-targeting chimeras.” The article details the intricate chemical and biological experiments that substantiate this formidable leap in drug development science. As the scientific community digests these findings, anticipation mounts over how swiftly this innovative strategy will influence both pharmaceutical pipelines and clinical practices worldwide.
Subject of Research: Cells
Article Title: C36-mediated endocytosis of proteolysis-targeting chimeras
News Publication Date: April 21, 2025
Web References: http://dx.doi.org/10.1016/j.cell.2025.03.036
References:
Wang, Z., Pan, B.-S., Manne, R.K., Chen, J., Lv, D., Wang, M., Tran, P., Weldemichael, T., Yan, W., Zhou, H., Martinez, G.M., Shao, J., Hsu, C.-C., Hromas, R., Zhou, D., Qin, Z., Lin, H.-K., Li, H.-Y. (2025). C36-mediated endocytosis of proteolysis-targeting chimeras. Cell. https://doi.org/10.1016/j.cell.2025.03.036
Image Credits: Not provided
Keywords
Drug discovery, Discovery research, Cancer medication, Drug research, Medicinal chemistry, Drug therapy, Cancer research, Cellular proteins, Personalized medicine, Brain cancer, Chemical reactions
