John C Jewett

John C Jewett

Associate Professor, Chemistry and Biochemistry-Sci
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
(520) 626-3627

Work Summary

Work Summary

We seek to develop tools and strategies to expedite the understanding and treatment of the dengue virus. These advances will be transferable to other areas of virology and biochemistry. Along these lines, we are engaged in three core synergistic projects to answer the following questions: (1) Do unnatural metabolites incorporated into DENV serve as reporters for host-pathogen interactions? (2) What are the host-pathogen interactions in DENV that are targetable for diagnosis or treatment? (3) Is there a chemical reaction between two small molecules that reports on the interaction between DENV and host proteins?

Research Interest

Our goal is to merge the fields of synthetic organic chemistry with virology. We develop new reactions (and re-appropriate old ones) to gain insight into how viruses infects new host cells. Additionally, we are working to develop new methods to probe protein-protein interactions through the use of small molecules.Viruses can rapidly evolve and new tools are required to meet this ever-changing threat. While vaccinations have tamed many historically deadly viral diseases, there are still rogue viruses for which no vaccination strategy is available. Dengue virus (DENV), the virus that is responsible for dengue fever, hemorrhagic fever, and shock syndrome, is one such pathogen. The WHO estimates that the mosquito-borne pathogen infects over 50 million people each year. With a rapid increase in severe, potentially fatal, disease forms, DENV poses a significant risk to the 2.5 billion people who live in DENV endemic regions.


He, J., Kimani, F. W., & Jewett, J. C. (2015). A Photobasic Functional Group. Journal of the American Chemical Society, 137(31), 9764-7.

Controlling chemical reactivity using light is a longstanding practice within organic chemistry, yet little has been done to modulate the basicity of compounds. Reported herein is a triazabutadiene that is rendered basic upon photoisomerization. The pH of an aqueous solution containing the water-soluble triazabutadiene can be adjusted with 350 nm light. Upon synthesizing a triazabutadiene that is soluble in aprotic organic solvents, we noted a similar light-induced change in basicity. As a proof of concept we took this photobase and used it to catalyze a condensation reaction.

Siegrist, M. S., Whiteside, S., Jewett, J. C., Aditham, A., Cava, F., & Bertozzi, C. R. (2013). D-amino acid chemical reporters reveal peptidoglycan dynamics of an intracellular pathogen. ACS Chemical Biology, 8(3), 500-505.

PMID: 23240806;PMCID: PMC3601600;Abstract:

Peptidoglycan (PG) is an essential component of the bacterial cell wall. Although experiments with organisms in vitro have yielded a wealth of information on PG synthesis and maturation, it is unclear how these studies translate to bacteria replicating within host cells. We report a chemical approach for probing PG in vivo via metabolic labeling and bioorthogonal chemistry. A wide variety of bacterial species incorporated azide and alkyne-functionalized d-alanine into their cell walls, which we visualized by covalent reaction with click chemistry probes. The d-alanine analogues were specifically incorporated into nascent PG of the intracellular pathogen Listeria monocytogenes both in vitro and during macrophage infection. Metabolic incorporation of d-alanine derivatives and click chemistry detection constitute a facile, modular platform that facilitates unprecedented spatial and temporal resolution of PG dynamics in vivo. © 2012 American Chemical Society.

Jensen, S. M., Kimani, F. W., & Jewett, J. C. (2016). Light-Activated Triazabutadienes for the Modification of a Viral Surface. Chembiochem : a European journal of chemical biology, 17(23), 2216-2219.

Chemical crosslinking is a versatile tool for the examination of biochemical interactions, in particular host-pathogen interactions. We report the critical first step toward the goal of probing these interactions by the synthesis and use of a new heterobifunctional crosslinker containing a triazabutadiene scaffold. The triazabutadiene is stable to protein conjugation and liberates a reactive aryl diazonium species upon irradiation with 350 nm light. We highlight the use of this technology by modifying the surface of several proteins, including the dengue virus envelope protein.

Kimani, F. W., & Jewett, J. C. (2015). Water-soluble triazabutadienes that release diazonium species upon protonation under physiologically relevant conditions. Angewandte Chemie (International ed. in English), 54(13), 4051-4.

Triazabutadienes are an understudied structural motif that have remarkable reactivity once rendered water-soluble. It is shown that these molecules readily release diazonium species in a pH-dependent manner in a series of buffer solutions with pH ranges similar to those found in cells. Upon further development, we expect that this process will be well suited to cargo-release strategies and organelle-specific bioconjugation reactions. These compounds offer one of the mildest ways of generating diazonium species in aqueous solutions.

Swarts, B. M., Holsclaw, C. M., Jewett, J. C., Alber, M., Fox, D. M., Siegrist, M. S., Leary, J. A., Kalscheuer, R., & Bertozzi, C. R. (2012). Probing the mycobacterial trehalome with bioorthogonal chemistry. Journal of the American Chemical Society, 134(39), 16123-16126.

PMID: 22978752;PMCID: PMC3466019;Abstract:

Mycobacteria, including the pathogen Mycobacterium tuberculosis, use the non-mammalian disaccharide trehalose as a precursor for essential cell-wall glycolipids and other metabolites. Here we describe a strategy for exploiting trehalose metabolic pathways to label glycolipids in mycobacteria with azide-modified trehalose (TreAz) analogues. Subsequent bioorthogonal ligation with alkyne-functionalized probes enabled detection and visualization of cell-surface glycolipids. Characterization of the metabolic fates of four TreAz analogues revealed unique labeling routes that can be harnessed for pathway-targeted investigation of the mycobacterial trehalome. © 2012 American Chemical Society.