University of Virginia
College of Arts & Sciences
The Tepe Lab
Our Research
We specialize in synthetic organic chemistry, medicinal chemistry, and chemical biology. The group’s focus is on studying protein degradation systems and developing small molecules to alter them. We also create novel ways to synthesize natural products and their derivatives as possible therapeutic leads. Our overall goal is to develop new therapies for cancer and neurodegenerative diseases.
Synthetic Organic Chemistry:
The Tepe lab makes natural products that are difficult to synthesize and therefore have never been made before! Students utilize various synthetic chemical techniques to develop the steps to make their desired product in a novel and exciting way. Once synthesized, these natural products can be tested for various biological activities, allowing us to better understand the potential for naturally occurring molecules as possible disease therapeutics.
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George, Dare; Tepe, Jetze J. Total Synthesis of Nagelamide W. Journal of Organic Chemistry, 2023, 88, 13, 9306–9312.
Savelson, Evan; Tepe, Jetze J. Accessing Highly Oxidized Imidazolidinone Cores via a Curtius Rearrangement: Total Synthesis of Colensolide A. Organic Letters 2023, 25, 3698–3701.
In doing these syntheses, students are also developing new chemical methods that can also be applied to a wide array of chemistry such as other natural product syntheses.
Hubbell, Grace E.; Tepe, Jetze J. Rh(III)-catalyzed C-H activation/annulation of benzo- hydroxamates and 2-imidazolones: access to urea-fused-dihydroisoquinolone scaffolds reminiscent of pyrrole-alkaloid natural products, Organic Letters, 2022, 24, 6740–6744.
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Savelson, Evan; Tepe, Jetze J. One-Pot Friedel−Crafts/Robinson−Gabriel Synthesis of the Indole-Oxazole Scaffold and its Application to the Synthesis of Breitfussins C, G, and H, Journal of Organic Chemistry, 2022, 88, 755–761.
Medicinal Chemistry:
Due to their flexible nature, and lack of binding pockets, intrinsically disordered proteins (IDPs) cannot be targeted in the same manner as typical structured proteins can. Instead, the Tepe lab tries to modulate the activity of dysregulated IDPs by inducing their degradation thereby restoring cellular proteostasis. To do this, we are developing small molecules that can target and alter the activity of the 20S proteasome, one of the main degradation systems for these proteins. Students working in medicinal chemistry are rapidly developing new small molecule scaffolds that can be used to create new 20S proteasome modulators. They use in-silico docking models and a combination of chemical synthetic and biological techniques and knowledge to design and synthesize and test the small molecules for biological activity. Knowledge about the structure-activity relationships within the compound can be elucidated and used for further development.
Staerz, S. D.; Jones, C. L. and Tepe, Jetze J. Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α-Synucleinopathies. Journal of Medicinal Chemistry, 2022, 65, 6631–6642.
Jones, Corey L.; Njomen, Evert; Sjogren B.; Dexheimer, Thomas S. and Tepe, Jetze J. Small molecule enhancement of 20S proteasome activity targets intrinsically disordered proteins. ACS Chemical Biology 2017, 15;12(9):2240-2247.
Chemical Biology:
Modulation of the 20S proteasome is a new and under-explored area of biological chemistry. In the Tepe lab, students are using 20S proteasome modulators to selectively control the activity of the proteasome, which in turn allows them to study the role it has in different cellular processes. By increasing or decreasing the degradation activity of the 20S proteasome, we can work towards understanding the role that intrinsically disordered proteins (IDPs), the substrate of the 20S proteasome, play in various systems. These small molecules are also being developed as possible therapeutics in diseases where IDPs are over expressed, like Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), and various cancers.
Vanecek, Allison, S.; Mojsilovic-Petrovic, Jelena; Kalb, Robert, G.; Tepe, Jetze J. Enhanced Degradation of Mutant C9ORF72-Derived Toxic Dipeptide Repeat Proteins by 20S Proteasome Activation Results in Restoration of Proteostasis and Neuroprotection, ACS Chemical Neuroscience 2023, 14, 1439–1448.
