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Faculty Research Labs

Tharp Lab

The major focus of Dr. Jeffery Tharp’s lab is to develop peptides that have unique therapeutic and research applications. The lab is currently focused on developing cyclic peptides with anti-cancer and anti-viral properties.

diagram shows a drug target surrounding the unnatural amino acid

Novel Therapeutic Peptides

Cyclic peptides have many properties that make them ideal for use as therapeutics. Desirable properties of cyclic peptides include, for example, high target affinity and selectivity, and low toxicity. A common feature of many cyclic peptides that have been isolated from natural sources, such as bacteria and fungi, is the presence of one or more unnatural amino acids. These unnatural amino acids improve the peptide's ability to resist proteolytic degradation, and provide unique chemical and structural motifs that can greatly improve the binding properties of the peptide. The Tharp lab is developing technology to produce libraries of cyclic peptides containing diverse unnatural amino acids. These libraries can be used to rapidly identify novel cyclic peptides that bind to diverse drug targets. Our primary interest is in identifying cyclic peptides with anticancer and antiviral properties.   

engineered suppressor tRNA converts amino-acid-encoding codons into premature stop codons

Engineered Suppressor tRNAs

The genetic code is comprised of 64 codons. These include 61 amino-acid-encoding codons, and three “stop codons”. Instead of coding for an amino acid, stop codons tell the ribosome to terminate protein synthesis. Approximately 10¬–15% of genetic diseases are caused by mutations that convert amino-acid-encoding codons into stop codons. These mutations introduce premature stop codons (PSCs) into protein-coding genes, causing protein synthesis to terminate prematurely. Our lab is working to engineer novel suppressor tRNAs—tRNAs that prevent PSCs from terminating protein synthesis. These suppressor tRNAs have the potential to treat debilitating diseases that are caused by PSCs, such as cystic fibrosis and Duchenne muscular dystrophy.  

an engineered aminoacyl tRNA synthetase surrounds an unnatural amino acid

Genetic Code Reprogramming

In nature, proteins are made using only 22 different amino acids that have relatively limited chemical and structural diversity. However, by engineering the protein synthesis machinery of cells, methods have been developed to install diverse unnatural amino acids into proteins. The ability to install unnatural amino acids into proteins in living cells has revolutionized the field of protein chemistry. Several projects have been initiated in our lab with a focus on expanding the utility of genetic code reprogramming. These include: (1) engineering aminoacyl-tRNA synthetases to recognize new unnatural amino acids with useful properties, and (2) developing platforms to install multiple distinct unnatural amino acids into proteins. Using these tools we have the ability to probe complex biological systems with unprecedented precision.  

Current Research Funding

4R00GM141320-02 (Tharp, PI)
Genetically encoded bicyclic peptide libraries for the discovery of novel antiviral agents

Recent Publications

J. T. Hampton*, T. J. Lalonde*, J. M. Tharp*, Y. Kurra, Y. R. Alugubelli, C. M. Roundy, G. L. Hamer, S. Xu, W. R. Liu, A novel regioselective approach to cyclize phage-displayed peptides in combination with epitope-directed selection to identify a potent neutralizing macrocyclic peptide for SARS-CoV-2. ACS Chem. Biol. 2022, 17 (10), 2911–2922.

J. M. Tharp, O. Vargas-Rodriguez, A. Schepartz, D. Söll, Genetic encoding of three distinct noncanonical amino acids using reprogrammed initiator and nonsense codons. ACS Chem. Biol. 2021, 16 (4), 766–774.

J. M. Tharp*, J. T. Hampton*, C. A. Reed*, A. Ehnbom, P.-H. C. Chen, J. S. Morse, Y. Kurra, L. M. Pérez, S. Xu, W. R. Liu, An amber obligate active site-directed ligand evolution technique for phage display. Nat. Commun. 2020, 11, 1392.

J. M. Tharp, O. Ad, K. Amikura, F. R. Ward, E. M. Garcia, J. H. D. Cate, A. Schepartz, D. Söll, Initiation of protein synthesis with noncanonical amino acids in vivo. Angew. Chem. Int. Ed. 2020, 59 (8), 3122–3126.

View a full list of publications

Research Team

62443-Tharp, Jeffery

Jeffery M. Tharp, PhD

Assistant Professor of Biochemistry & Molecular Biology

Read Bio

Jenny Flora

Research Technician