2025 – DR. Hendrik Luesch
Natural Product Reports
The pipeline of anticancer agents from marine cyanobacteria are described, highlighting critical steps from discovery towards development, including the identification of the molecular target and mechanism of action, and solving the supply problem. The center triangle depicts the key elements of a successful marine natural products discovery campaign, including a new genetic resource that encodes novel structures, the identification of the target and mechanism of action, and solving the supply problem usually through chemical synthesis, exemplified by the tubulin-targeting gatorbulin-1. The background shows additional structures of marine cyanobacterial anticancer agents discussed in the review by Luesch et al.
2024 – Dr. Robert Huigens
Organic & Biomolecular Chemistry
Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules.
2024 – Dr. Chengguo (CX) Xing
Chemical Research in Toxicology
UF Health Cancer Center researchers bolstered their findings that kava may reduce lung cancer risk caused by tobacco smoke. The team discovered a genetic variation that could help predict those likely to have the greatest response to kava intervention
2024 – Dr. Hendrik Luesch
Chemistry a European Journal
Marine natural product on target: GPCRs are prime targets for drug discovery, representing targets of over 40% of approved drugs. The cover illustrates tumonolide, a new marine natural product, docked into the binding pocket of the tachykinin receptor 2 (TACR2). The TACR2-selective GPCR inhibitor was isolated from a marine cyanobacterium, and its structure, including the absolute configuration depicted on the ocean floor, was elucidated through various spectroscopic and computational methods.
2024 – Dr. Lina Cui
ACS Medicinal Chemistry Letters
Overexpression of heparanase (HPSE) is associated with various types of cancer, inflammation, and immune disorders, making it an emerging therapeutic target. Few small-molecule inhibitors have progressed to preclinical or clinical stages, leaving a gap in HPSE drug discovery. In this study, a novel small molecule that can inhibit HPSE activity was discovered through high-throughput screening. Computational tools were employed to elucidate the structure–activity relationship of the hit compound, offering insights into the design of future small-molecule inhibitors targeting HPSE.
2024- Dr. Lina Cui
Journal of Medicinal Chemistry
This article describes the development of a positron emission tomography (PET) probe that can be used for translational imaging of cellular senescence in various age-related diseases.
2024 – Drs. Hendrik Luesch & Yousong Ding
Organic Letters
Dolastatin 10, a potent tubulin-targeting marine anticancer natural product, provided the basis for the development of six FDA-approved antibody–drug conjugates. Through the screening of cyanobacterial Caldora penicillata environmental DNA libraries and metagenome sequencing, we identified its biosynthetic gene cluster. Functional prediction of 10 enzymes encoded in the 39 kb cluster supports the dolastatin 10 biosynthesis. The nonheme diiron monooxygenase DolJ was biochemically characterized to mediate the terminal thiazole formation in dolastatin 10.
2023 – Dr. RobERT Huigens
RSC Medicinal Chemistry
In this study, we report the design, chemical synthesis, and biological investigations of nitroarene-based HP prodrugs that leverage intracellular nitroreductase (NTR) enzymes for activation and subsequent release of active HP antibacterial agents. Based on the findings in this study, we believe that HP-nitroarene prodrugs could provide a future avenue to develop useful agents that eradicate antibiotic resistant bacteria.
2023 – Dr. Yousong Ding & Dr. Hendrik Luesch
Journal of Natural Products
Lyngbyastatin (Lbn) 1 and 3 were identified from the field-collected marine cyanobacterium Okeania sp. Their biosynthetic gene cluster was predicted from the metagenome-assembled genome and confirmed by bioinformatic analysis and biochemical studies of selected adenylation domains. Two Lbn-like gene clusters were further mined from publicly available cyanobacterial genomes.
2022- Dr. lina cui
Bioconjugate Chemistry
Heparanase is an enzyme involved in tissue healing, cancers, inflammation, and viral infection. Its importance as a therapeutic target warrants further study, but chemistry for heparanase-activatable probes and drugs is limited. Here, a universal scaffold is reported to facilitate the development of heparanase-responsive probes and drugs.
2022 – Dr. Hendrik Luesch
ACS Infectious Diseases
Apratoxin S4 in action against SARS-CoV-2: This host-directed antiviral shuts off spike protein production and trafficking (top) and prevents double membrane vesicle formation and assembly of progeny virions (bottom).
2022 – Dr. Yousong Ding
RSC Chemical Biology
The nitroreductase of Haemophilus influenzae metabolizes clinically used nitroimidazoles, generates dimeric metabolites and anaerobically sensitizes an E. coli mutant to antibiotics. UF College of Pharmacy researchers further uncover its biochemical and structural details.
2021- Dr. Lina cui
Journal of Medicinal Chemistry
A self-immobilizing near-infrared (NIR) fluorogenic probe enables the efficient noninvasive detection of cellular senescence, a cellular response mechanism for various stresses that develop during therapy or aging. The cover art is attached.
2021 – Dr. Yousong Ding
iScience
This review discusses multiple strategies and examples in using native and engineered biosynthetic enzymes for the production of both ribosomally and nonribosomally synthesized peptides and the screening for bioactive leads. These peptides are an important class of bioactive molecules for drug research. Chemical synthesis has been established for some PNPs and their analogues but all suffered from negative environmental impacts and unsustainability. The use of native and engineered enzymes will aid the development of more green approaches for chemical synthesis in general.
2021 – DR. ROBERT HUIGENS
Journal of Medicinal Chemistry
UF medicinal chemists report promising results from a study focused on new ways to of treating several types of antibiotic-resistant bacteria, advances that may help in the battle against MRSA, tuberculosis and other infectious pathogens.
2021 – DrS. chris Mccurdy and Hebaalla agha
RSC Medicinal Chemistry
This review discusses the principles of molecular imaging with known sigma-1 receptor (S1R) radioligands, along with S1Rs labeling applications in various disease states. Highlighted here are S1R radioligands that have demonstrated considerable potential as biomarkers in humans with the ultimate goal of better healthcare outcomes.
2020 – Dr. Chris McCurdy
ACS Pharmacology and Translational Science
Mitragynine is the most abundant alkaloid in kratom (Mitragyna speciosa) which is widely consumed for the self-treatment of pain and opioid withdrawal symptoms. An active metabolite of mitragynine, 7-hydroxymitragynine, is a potent and efficacious opioid. Exclusively in human plasma, 7-hydroxymitragynine metabolizes to the even more potent opioid, mitragynine pseudoindoxyl.
2020 – dr. yousong ding
ACS Chemical Biology
This work reports the biochemical, genetic, and structural characterization of cyanobacterial dihydroxyacid dehydratase essential to the biosynthesis of branched-chain amino acids. Selective inhibition of the cyanobacterial enzyme by aspterric acid but not tartronic acid leads to the growth inhibition of representative bloom-forming cyanobacterial strains, a promising strategy for bloom management.
2020 – Dr. Hendrik Luesch
ACS Chemical Neuroscience
Surfing across the blood-brain barrier with a purpose and a splash: The marine natural product and potent class I HDAC inhibitor largazole has activity against glioblastoma cells and induces neuroprotective and antiproliferative functional responses in the brain through modulation of gene expression of entire networks underlying CNS diseases.
2020 – Dr. Chengguo Xing
Cancer Prevention Research
Smoking is the dominant risk factor for lung cancer, but many smokers fail to quit due to addiction. An intervention, not only inhibiting tobacco-associated lung carcinogenesis but also reducing smoking, may be necessary to minimize lung cancer risk. Built upon the stimulating epidemiological indication, ample lab animal lung carcinogenesis data, and armed with innovative mechanism-based non-invasive quantitative biomarkers, our group in collaboration with clinicians performed a pilot human trial of one-wee kava use among addicted smokers. The results published in Cancer Prevention Research for the first time demonstrate the potential of kava to not only reduce the risk of lung carcinogenesis but also help smokers reduce tobacco use.
2020 – Dr. Lina Cui
ChemBioChem
Fluorophores are greatly influenced by their environment. In their full paper, L. Cui et al. show that triggering the aggregation of a self‐condensing scaffold labeled with a fluorophore induces changes in the emission spectrum, polarization, and lifetime. The aggregates exhibited a shorter lifetime detectable in cells by fluorescence lifetime imaging microscopy, thus suggesting that triggered aggregation strategies can be used in the probes for various biological events through lifetime imaging.
2020 – DR. ROBERT HUIGENS
ACS Infectious Diseases
This cover shows a novel antiplasmodial agent attacking Plasmodium falciparum parasites in infected red blood cells. This new compound was re-engineered from the indole alkaloid yohimbine using a “ring distortion” chemical synthesis approach reported by the Huigens lab. Artwork created by Ella Marushchenko
2020 – DR. ROBERT HUIGENS
Journal of Medicinal Chemistry
Re-engineering biological activities of the plant-derived indole alkaloid vincamine through dramatic synthetic alterations of its complex structure for target-based screens by the Huigens lab and co-workers at the University of Florida. Artwork created by Ella Marushchenko.
2019 – DR. HENDRIK LUESCH
Organic Letters
The cover image illustrates the multidisciplinary research that linked a natural product discovered from the depicted marine cyanobacteria to GPCR modulation. The portrayed peptide, amantamide, was isolated, synthesized, and characterized as a selective CXCR7 agonist. Molecular modeling of amantamide provides the starting point for rational optimization.
2019 – Dr. yousong ding
ChemBioChem
The front cover picture shows a versatile biocatalytic synthesis of hydroxylated di‐N‐methylated aromatic diketopiperazines (ADKPs). Di‐N‐methylated ADKPs were synthesized from two amino acids with TxtA and TxtB (yellow) from Streptomyces scabies, or from ADKP with one N‐methyltransferase Amir_4628 (green) from Actinosynnema mirum. Human methionine adenosyltransferase hMAT2A (purple) was recruited to synthesize the methyl donor SAM. The P450 TxtC (pink) along with the NADPH‐recycling glucose dehydrogenase (cyan) from Bacillus subtilis promoted aliphatic and/or aromatic C−H hydroxylation on di‐N‐methylated ADKPs.
2018 – DR. HENDRIK LUESCH
ChemBioChem
The cover feature picture shows Ahp-cyclodepsipeptides, the producing marine cyanobacterium overgrowing a coral, and the compounds’ anticancer effects. These cyclodepsipeptides inhibit human neutrophil elastase and, as a consequence, the migration of invasive breast cancer cells through the modulation of gene expression and proteolytic processing of membrane proteins.
2017 – DR. ROBERT HUIGENS
Organic Biomolecular Chemistry
The Huigens lab reports a new series of antimicrobial peptide-inspired NH125 analogues that rapidly kill bacterial and fungal pathogens, including surface-attached biofilms.
2017 – DR. ROBERT HUIGENS
Chemistry – A European Journal
The 2‐position of the halogenated quinoline (HQ) scaffold can be dramatically tuned through diverse and practical synthetic pathways, including reductive amination and alkylation reactions. New HQs discovered during these investigations potently eradicate methicillin‐resistant Staphylococcus aureus (MRSA), methicillin‐resistant Staphylococcus epidermidis (MRSE) and vancomycin‐resistant Enterococcus faecium (VRE) biofilms, which display high levels of tolerance towards conventional antibiotic therapies. The background image is reproduced with permission and copyright of the British Editorial Society of Bone and Joint Surgery (Bone Joint J. 2013, 95B, 678–682; Figure 2 b).
2017 – DR. ROBERT HUIGENS
ChemBioChem
The cover picture shows the destruction of a bacterial membrane by a new NH125 analogue. Through chemical synthesis and biological evaluation, the Huigens lab has identified potent N‐arylated compounds that rapidly kill MRSA persister cells and eradicate surface‐attached bacterial biofilms of multiple Gram‐positive pathogens. These N‐arylated NH125 analogues demonstrated enhanced activity in killing persister cells and eradicating biofilm when tested alongside a structurally diverse panel of membrane‐active agents.
2017 – DR. ROBERT HUIGENS
Chemistry – A European Journal
A tryptoline‐based ring distortion strategy enabled rapid access to an array of complex and diverse molecular scaffolds synthesized from the indole alkaloid, yohimbine. During these investigations, 70 complex and diverse small molecules were synthesized and subjected to a panel phenotype screen. These efforts led to the identification of several biologically active hit compounds, including one compound that demonstrates HIF‐dependent antiproliferative activity in HCT116 (colorectal cancer) cells.
2012 – DR. HENDRIK LUESCH
Current Drug Targets
Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. Secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.
2010 – dR. hENDRIK lUESCH
Chemistry – A European Journal
Natural products are secondary metabolites that confer survival advantages to the producing organism. Many require activation before they exert their biological effects, perhaps as part of the organism's self‐resistance strategy or to aid targeted delivery. In this Concept article Luesch and Kwan outline several examples of “Weapons in Disguise”, natural products that use protecting group chemistry or intricate chemical cascades for activation beyond simple “prodrug” paradigms.
2010 – DR. HENDRIK LUESCH
The Journal of Pharmacology and Experimental Therapeutics
The Luesch lab previously described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases the most potent natural inhibitor of class I histone deacetylases (HDACs), validated targets for cancer therapy. The cover highlights structure-activity studies using biochemical and molecular docking approaches. The article describes the characterization of the anticancer activity of largazole using in vitro and in vivo cancer models, including comparative transcriptomics, pharmacology, biochemical validation, stability, and efficacy studies.
2010 – dR. hENDRIK lUESCH
Natural Product Reports
Hendrik Luesch’s discovery of largazole and its producing cyanobacterium are featured in this annual Marine Natural Products review and on the journal cover, respectively.
2006 – dR. HENDRIK LUESCH
Molecular BioSystems
Genome-scale analysis has been extended from gene expression profiling to parallel cell-based functional profiling, allowing the characterization of gene function and small molecule actions in yeast and in mammalian cells.
2006 – Dr. Hendrik luesch
Nature Chemical Biology
This is the first report that uses an unbiased functional genomics approach in cancer cells to study the mode of action of a potent cyanobacterial cytotoxin and also visualizes “apratoxin A in action” in zebrafish.