The newly identified fungus, named Periglandula clandestina, was found living within morning glory plants (Ipomoea tricolor), a species celebrated not only for its ornamental beauty but also for its biochemical complexity. Morning glories have been known to carry intricate chemical defenses, particularly ergot alkaloids, protective compounds produced by fungal symbionts. These alkaloids share structural similarities to the synthetic modifications found in LSD, a drug historically explored for its psychoactive and therapeutic properties. Hazel’s keen observation of subtle fuzz on the seed coats of morning glory plants led to the first hints that this elusive fungal partner was finally within reach of scientific characterization.

Under the auspices of a WVU Davis College Student Enhancement Grant, Hazel undertook the preparation of fungal DNA isolates, initiating genome sequencing efforts that ultimately substantiated the presence of a new fungal species. The molecular data, now cataloged in public genomic repositories, validate the classification of Periglandula clandestina and lay the foundation for future biochemical and pharmacological studies. “Sequencing a genome of this caliber is no small feat,” commented Professor Panaccione. “It’s extraordinary that a student could shepherd a project from discovery to genetic characterization.”

The genus Periglandula is a group of endophytic fungi known for their mutualistic relationship with morning glories. These fungi inhabit specialized structures on the plant’s seeds and tissues, synthesizing ergot alkaloids that contribute to the plants’ defense mechanisms against herbivory and disease. Ergoline alkaloids, produced exclusively by fungi, have a storied history — notably in the 20th century, when Swiss chemist Albert Hofmann synthesized LSD by modifying similar natural products derived from ergot fungi found in rye. Hofmann speculated decades ago that fungi colonizing morning glories might be sources of these LSD-like compounds, but despite intensive research, the responsible fungal species remained unidentified—until now.

Periglandula clandestina’s efficiency in producing large quantities of ergot alkaloids positions it as a compelling candidate for drug development pipelines. Ergot alkaloids have diverse and potent biological activities, ranging from vasoconstrictive to neurotropic effects. While ergot derivatives have traditionally been used to manage migraines, uterine hemorrhaging, and Parkinson’s disease symptoms, their clinical application often comes with significant side effects. Contemporary research aims to harness these compounds’ beneficial pharmacodynamics while minimizing toxicity, an endeavor Periglandula clandestina may substantially accelerate.

The discovery holds further intrigue because it solves a decades-old mystery in ethnobotany and fungal biology: how morning glories attain their psychedelic properties. The high concentrations of lysergic acid derivatives found in these plants had long suggested fungal involvement, but the actual fungus remained “clandestine,” evading detection. Corinne Hazel’s meticulous lab work and innovative application of genomic tools now bring clarity to this biological enigma. “The name fits perfectly,” said Panaccione. “‘Clandestina’ reflects the fungus’s elusive nature and the achievement in finally identifying it.”

Beyond its biochemical significance, this finding highlights the value of student-led research and the integration of molecular biology with classical mycology and plant sciences. Hazel’s journey—from noticing faint fungal growth on seed coats to contributing to a peer-reviewed Mycologia publication—epitomizes the potential for talent and opportunity to revolutionize scientific understanding. Her ongoing investigations aim to refine culturing techniques for this slow-growing fungus, an important step toward large-scale biochemical extraction and analysis.

More broadly, the discovery invites questions about the diversity of Periglandula fungi among other morning glory species and their respective alkaloid profiles. The possibility of undiscovered fungal symbionts with unique alkaloid biosynthesis pathways could transform both agricultural biotechnology and pharmacology. Since ergot alkaloids can have toxic effects on humans and livestock in unregulated forms, understanding and harnessing fungal metabolism presents dual imperatives: enhancing medication safety profiles and mitigating risks in crop production.

The symbiotic relationship between morning glories and Periglandula clandestina exemplifies a sophisticated evolutionary mechanism. The fungus benefits from protected niches within the plant, while the host gains chemical defenses and potentially enhanced survival. This mutualism underscores the broader interactive complexity of plant-fungal ecosystems and their unexplored potential for natural product discovery.

As research progresses, Periglandula clandestina may play a pivotal role in the development of novel psychedelics and pharmaceuticals aimed at treating an array of psychiatric disorders including depression, post-traumatic stress disorder, and addiction—areas where current therapeutic strategies remain limited. By delving into the fungus’s genetic blueprint and biochemical output, scientists hope to isolate compounds that maintain therapeutic efficacy with reduced adverse effects, a critical advancement amid growing interest in psychedelic-assisted therapies.

In summary, the identification and genomic characterization of Periglandula clandestina represent a landmark in fungal biology with promising implications for neuroscience and medicine. This discovery not only validates historical hypotheses about the origins of psychoactive compounds in morning glories but also opens a new frontier for biotechnological exploration of ergot alkaloids. Corinne Hazel’s groundbreaking contribution reflects the power of curiosity-driven research and may well inspire a renaissance in natural product drug discovery derived from plant-fungal symbioses.

Subject of Research: A newly discovered species of fungus, Periglandula clandestina, symbiotic with morning glory plants producing ergot alkaloids similar to LSD.

Article Title: A new species of Periglandula symbiotic with the morning glory Ipomoea tricolor

News Publication Date: 22-Apr-2025

Web References:
http://dx.doi.org/10.1080/00275514.2025.2483634

References:
Hazel, C., & Panaccione, D. (2025). A new species of Periglandula symbiotic with the morning glory Ipomoea tricolor. Mycologia. DOI: 10.1080/00275514.2025.2483634

Image Credits: WVU Photo/Brian Persinger

Keywords: Drug studies, Pharmacology, Research programs, Drug research, Affective disorders, Psychiatric disorders, Mental health, Cognitive disorders, Depression, Substance related disorders, Drug addiction, Cocaine addiction, Alcoholism, Narcotics addiction, Withdrawal symptoms, Illicit drugs, Mycology

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