Research Summary

The Gestwicki Laboratory is interested in molecular chaperones, protein homeostasis and protein misfolding disorders. To approach the big questions in this area, we use a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors. We use these chemical probes to acutely perturb chaperone functions, revealing how these systems normally protect from cancer and neurodegeneration. Many of our chemical probes target allosteric and protein-protein interaction sites on the molecular chaperones and we have a significant interest in discovering inhibitors of "difficult" targets. We hope to better understand the logic of protein folding and misfolding and use this information to design more effective therapies.

Research Funding

  • August 15, 2016 - May 31, 2018 - Activation of the 20S Proteasome to Normalize Tau Homeostasis, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AG053619
  • June 1, 2014 - February 28, 2018 - Exploration of Molecular Chaperone Complexes During Active Protein Triage, Co-Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM109896
  • February 1, 2012 - January 31, 2014 - Natural Product-Inspired Method for Enhancing HIV Protease Inhibitors, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AI098431
  • August 1, 2012 - March 31, 2013 - Chemical Probes and Chaperone-Accelerated Turnover of Tau, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AG042813

Education

State University of New York - Fredonia, B.S., 1997, Chemistry
University of Wisconsin – Madison (with Laura L. Kiessling), PhD, 2002, Biochemistry
Stanford University (with Gerald R. Crabtree), 2005, Post-doctoral, Chemical Biology

Honors & Awards

  • 2020
    Everson Lecture, University of Wisconsin-Madison
  • 2019
    Chair, Bioorganic Chemistry GRC
  • 2018
    Elected Fellow, Cell Stress Society International (CSSI)
  • 2018
    Keynote Speaker, 9th International Symposium on Heat Shock Proteins in Biology and Medicine
  • 2018, 2019
    Dean's Apple Award, Outstanding Teaching in UCSF School of Pharmacy
  • 2017
    Director, Chemistry & Chemical Biology Ph.D. Program UCSF
  • 2015
    UCSF School of Pharmacy, Excellence in Teaching
  • 2014
    Named "Young Innovator" at UCSF
  • 2012
    Elected Fellow, American Association for the Advancement of Science (AAAS)
  • 2009
    National Science Foundation CAREER award

Selected Publications

  1. Retraction of "Enantioselective Organocatalytic Hantzsch Synthesis of Polyhydroquinolines".  View on PubMed
  2. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.  View on PubMed
  3. Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.  View on PubMed
  4. Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels.  View on PubMed
  5. Tao J, Berthet A, Citron YR, Tsiolaki PL, Stanley R, Gestwicki JE, Agard DA, McConlogue L Hsp70 chaperone blocks a-synuclein oligomer formation via a novel engagement mechanism.  View on PubMed
  6. Abrams J, Arhar T, Mok SA, Taylor IR, Kampmann M, Gestwicki JE Functional genomics screen identifies proteostasis targets that modulate prion protein (PrP) stability.  View on PubMed
  7. Makley LN, Johnson OT, Ghanakota P, Rauch JN, Osborn D, Wu TS, Cierpicki T, Carlson HA, Gestwicki JE Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods.  View on PubMed
  8. Dutta T, Singh H, Gestwicki JE, Blatch GL Exported plasmodial J domain protein, PFE0055c, and PfHsp70-x form a specific co-chaperone-chaperone partnership.  View on PubMed
  9. Schuller M, Correy GJ, Gahbauer S, Fearon D, Wu T, Díaz RE, Young ID, Martins LC, Smith DH, Schulze-Gahmen U, Owens TW, Deshpande I, Merz GE, Thwin AC, Biel JT, Peters JK, Moritz M, Herrera N, Kratochvil HT, Aimon A, Bennett JM, Neto JB, Cohen AE, Dias A, Douangamath A, Dunnett L, Fedorov O, Ferla MP, Fuchs M, Gorrie-Stone TJ, Holton JM, Johnson MG, Krojer T, Meigs G, Powell AJ, Rack JGM, Rangel VL, Russi S, Skyner RE, Smith CA, Soares AS, Wierman JL, Zhu K, Jura N, Ashworth A, Irwin J, Thompson MC, Gestwicki JE, von Delft F, Shoichet BK, Fraser JS, Ahel I Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.  View on PubMed
  10. Nadel CM, Ran X, Gestwicki JE Luminescence complementation assay for measurement of binding to protein C-termini in live cells.  View on PubMed
  11. Schwarz DMC, Williams SK, Dillenburg M, Wagner CR, Gestwicki JE A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1.  View on PubMed
  12. Bengoechea R, Findlay AR, Bhadra AK, Shao H, Stein KC, Pittman SK, Daw JA, Gestwicki JE, True HL, Weihl CC Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy.  View on PubMed
  13. Shao H, Oltion K, Wu T, Gestwicki JE Differential scanning fluorimetry (DSF) screen to identify inhibitors of Hsp60 protein-protein interactions.  View on PubMed
  14. Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Blecha JE, VanBrocklin HF, Seo Y, Sayeed M, Feldman BJ, Aggarwal R, Behr SC, Shao H, Wilson DM, Villanueva-Meyer JE, Gestwicki JE, Evans MJ A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography.  View on PubMed
  15. Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, Tsai S, Park JI Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability.  View on PubMed
  16. Jackson JW, Rivera-Marquez GM, Beebe K, Tran AD, Trepel JB, Gestwicki JE, Blagg BSJ, Ohkubo S, Neckers LM Pharmacologic dissection of the overlapping impact of heat shock protein family members on platelet function.  View on PubMed
  17. Wu PK, Hong SK, Chen W, Becker AE, Gundry RL, Lin CW, Shao H, Gestwicki JE, Park JI Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability.  View on PubMed
  18. Singh JK, Hutt DM, Tait B, Guy NC, Sivils JC, Ortiz NR, Payan AN, Komaragiri SK, Owens JJ, Culbertson D, Blair LJ, Dickey C, Kuo SY, Finley D, Dyson HJ, Cox MB, Chaudhary J, Gestwicki JE, Balch WE Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone.  View on PubMed
  19. Shao H, Gestwicki JE Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98.  View on PubMed
  20. Chen X, Li Y, Wang C, Tang Y, Mok SA, Tsai RM, Rojas JC, Karydas A, Miller BL, Boxer AL, Gestwicki JE, Arkin M, Cuervo AM, Gan L Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.  View on PubMed

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