Professor of Biology and Chemistry
Antimicrobial design; targeted protein degradation; mTORC1 inhibition; enzyme structure-function studies.
My laboratory uses approaches derived from both chemistry and biology. Projects include problems in inhibitor design, enzyme catalysis, protein degradation and the mechanism of visual disease. Techniques vary with the particular project, and can entail molecular biology, organic synthesis, protein crystallography and NMR spectroscopy as well as protein purification, enzyme kinetics and mutagenesis. Our ongoing projects are outlined below. For more information, please see the lab web site.
IMPDH-targeted antimicrobial discovery. Microbial infections are now the second leading cause of death worldwide. Many commonly used antibiotics have been rendered ineffective by the upsurge of drug resistance, and years of neglect have left a mere trickle of new antibiotics in the pipeline. New targets, and new drugs, are urgently needed. Although IMPDH inhibitors are used in immunosuppressive, cancer and antiviral therapy, as yet IMPDH inhibitors have not been exploited in antimicrobial applications because no bacterial-selective IMPDH inhibitors have been identified. We have been identified low nanomolar inhibitors of bacterial IMPDHs with >250 selectivity versus the human enzyme. These compounds display potent antibacterial activity against Mycobacterium tuberculosis. While the antibacterial activity of many of these compounds clearly derives from inhibition of IMPDH, other compounds also engage an additional target(s). Multi-target antibiotics have a greatly diminished risk of developing resistance than single target compounds, so the observation that the pharmacophore of IMPDH inhibition overlaps with that of another essential process is exciting. We are currently optimizing IMPDH inhibitors as well as identifying the unknown target(s) to provide a foundation for multi-target antibiotic development. The research team includes Greg Cuny (UHouston), Helena Boshoff (NIH), Andrzej Joachimiak (Argonne) and Joanna Goldberg (Emory).
Targeted protein degradation. A single over-arching strategy has been utilized in the rational design of drugs inducing target degradation: localization of the target protein to a ubiquitin E3 ligase with chimeric molecules consisting of a target recognition ligand linked to an E3 ligase binding ligand. These molecules induce ubiquitination and ultimate degradation of the target protein via the 26S proteasome. We have pioneered an alternative strategy where the recognition ligand is tethered to a moiety that binds to the 20S proteasome, inducing degradation while bypassing ubiquitination. We are now further developing this methodology. We expect that this work will also yield important new insights into the pathways of protein quality control.
A novel mTORC1 inhibitor. Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways is common feature of the diseases of aging. mTORC1 inhibition is a promising treatment strategy for these diseases. We discovered a small molecule (CB3A) that inhibits mTORC1 signaling via a novel mechanism. CB3A is a more effective, if less potent, inhibitor of translation than the eponymous mTORC1 inhibitor rapamycin. We are delineating the mechanism of CB3A action in order to identify which diseases are most likely to respond to a CB3A-based treatment strategy. Understanding the mechanism of CB3A inhibition is also likely to identify new facets of mTORC1 regulation.
- Sun XE, Hansen BG, Hedstrom L. "Kinetically Controlled Drug Resistance: How Penicillium brevicompactum survives mycophenolic acid." J Biol Chem. 2011;286(47):40595-600.
- Long MJ, Gollapalli DR, Hedstrom L. "Inhibitor mediated protein degradation." Chem Biol. 2012;19(5):629-37.
- Mandapati K, Gorla SK, House AL, McKenney ES, Zhang M, Rao SN, Gollapalli DR, Mann BJ, Goldberg JB, Cuny GD, Glomski IJ, Hedstrom L. (2014). "Repurposing cryptosporidium inosine 5'-monophosphate dehydrogenase inhibitors as potential antibacterial agents." ACS Med Chem Lett 5(8): 846-850.
- Makowska-Grzyska M, Kim Y, Maltseva N, Osipiuk J, Gu M, Zhang M, Mandapati K, Gollapalli DR, Gorla SK, Hedstrom L, Joachimiak A. (2015). "A Novel Cofactor-binding Mode in Bacterial IMP Dehydrogenases Explains Inhibitor Selectivity." J Biol Chem 290(9): 5893-5911.
- Makowska-Grzyska M, Kim Y, Gorla SK, Wei Y, Mandapati K, Zhang M, Maltseva N, Modi G, Boshoff HI, Gu M, Aldrich C, Cuny GD, Hedstrom L, Joachimiak A. (2015). "Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds." PLoS ONE10(10): e0138976.
- Lawson AP, Long MJ, Coffey RT, Qian Y, Weerapana E, El Oualid F, Hedstrom L.. (2015). "Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes." Cancer Res 75(23): 5130-5142.
- Coffey RT, Shi Y, Long MJ, Marr MT 2nd, Hedstrom L. (2016). "Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling." J Biol Chem 291(10): 5221-5233.
- Shi Y, Long MJ, Rosenberg MM, Li S, Kobjack A, Lessans P, Coffey RT and Hedstrom L. (2016). "Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome." ACS Chem Biol. 2016, 11 (12), pp 3328–3337.
- Chacko S, Boshoff HIM, Singh V, Ferraris DM, Gollapalli DR, Zhang M, Lawson AP, Joachimiak A, Rizzi M, Mizrahi V; Cuny GD, and Hedstrom, L. (2018). Expanding benzoxazole based inosine 5’-monophosphate dehydrogenase (IMPDH) inhibitor structure-activity as potential anti-tuberculosis agents. J. Med. Chem. 61, 4739-4756.
- Rosenberg MM, Redfield AG, Roberts MF, and Hedstrom L. (2018). Dynamic characteristics of GMP reductase complexes revealed by high resolution 31P field cycling NMR relaxometry. Biochemistry 57, 3146-3154.
- Yu R, Kim Y, Maltseva N, Braunstein P, Joachimiak A and Hedstrom L. (2019) Oxanosine monophosphate is a covalent inhibitor of inosine 5’-monophosphate dehydrogenase. Chem. Res. Toxicol. 32, 456-466.
View Complete Publication List on PubMed: Liz Hedstrom