Research Summary

I have spent 33 years doing research in therapeutic sciences and biotechnology development, first 16 years at Genentech and then 8 years at Sunesis (a company I founded) prior to joining UCSF 9 years ago. At Genentech, my group was among the first to develop gain-of-function engineering of enzymes and proteins by site-directed mutagenesis and phage display. At Sunesis, we developed novel technologies for fragment-based drug discovery, notably the site-directed approach Tethering. My lab at UCSF has developed the N-terminomics technology to characterize the caspase products cleaved during apoptosis. We currently have what we believe is the largest database of proteins that are cleaved by caspases (~2,000 targets in all), as well as targets cleaved in specific cells and their precise cleavage sites identified. More recently, we have extended our proteomics work to serum using the subtiligase tagging technology. This has allowed us to dive to very low abundance proteins in serum. We have also engineered a new small molecule activated protease, called the SNIPer. We have built a catalytic tagging device called the NEDDylator to interrogate molecular binding partners in cellular pathways involving E3 ligases. Recently, we have developed a motif-specific scaffold strategy for producing synthetic monoclonal antibodies specific to post-translational modifications. I am also Director of the Small Molecule Discovery Center (SMDC) at UCSF, a core facility that offers UCSF researchers access to modern small molecule discovery technologies including high-throughput screening, fragment-based drug discovery, and hit-to-lead medicinal chemistry. We have also built the Antibiome Center for generation of renewable recombinant antibodies to the proteome.

Research Funding

  • September 24, 2014 - August 31, 2019 - Antibody Research Technology Center, Co-Investigator. Sponsor: NIH/NCI, Sponsor Award ID: P41CA196276
  • June 16, 2014 - May 31, 2019 - Affinity-directed tagging of protein binding partners in signaling, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01CA191018
  • April 1, 2007 - July 31, 2016 - Global Analysis of Proteolysis in Apoptosis, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01GM081051
  • March 1, 2014 - February 29, 2016 - Generation of recombinant thiopeptides to target antimicrobial-resistant bacteria, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AI111662

Education

University of California, Berkeley, CA, B.A., 1973, Biochemistry
Washington State University, Ph.D., 1979, Biochemistry
Washington State University, Postdoc, 1979-1980, Chemistry
Stanford University Medical School, Postdoc, 1980-1982, Biochemistry

Honors & Awards

  • 1979-1981
    Damon M. Runyon - Walter Winchell Postdoctoral Fellowship
  • 1990
    Pfizer Award (given by the American Chemical Society for achievements in enzyme chemistry)
  • 1998
    Recipient of the Christian B. Anfinsin Award presented by the Protein Society
  • 1998
    Recipient of the Vincent du Vignead Award given by the American Peptide Society
  • 1999
    Elected Member to the National Academy of Sciences
  • 2003
    Recipient of the Hans Neurath Award given by the Protein Society
  • 2006
    Perlman Lecture Award of the ACS biotechnology Division
  • 2017
    Named to first cohort of Chan Zuckerberg Biohub Investigators

Selected Publications

  1. Chen W, Mou KY, Solomon P, Aggarwal R, Leung KK, Wells JA Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy.  View on PubMed
  2. Tian R, Samelson AJ, Rezelj VV, Chen M, Ramadoss GN, Guo X, Kain AM, Tran QD, Lim SA, Lui I, Nunez J, Rockwood SJ, Liu N, Carlson-Stevermer J, Oki J, Maures T, Holden K, Weissman JS, Wells JA, Conklin B, Vignuzzi M, Kampmann M BRD2 inhibition blocks SARS-CoV-2 infection in vitro by reducing transcription of the host cell receptor ACE2.  View on PubMed
  3. Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1.  View on PubMed
  4. Wei J, Leung K, Truillet C, Ruggero D, Wells JA, Evans MJ Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling.  View on PubMed
  5. Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Lim SA, Zhou XX, Hobman TC, Kortemme T, Wells JA Engineered ACE2 receptor traps potently neutralize SARS-CoV-2.  View on PubMed
  6. Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, Zha BS, Schaefer K, Byrnes JR, Zhou J, Lui I, Liu J, Pance K, Zhou XX, Leung KK, Wells JA Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.  View on PubMed
  7. Zhou XX, Bracken CJ, Zhang K, Zhou J, Mou Y, Wang L, Cheng Y, Leung KK, Wells JA Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps.  View on PubMed
  8. Zhou J, Li S, Leung KK, O'Donovan B, Zou JY, DeRisi JL, Wells JA Deep profiling of protease substrate specificity enabled by dual random and scanned human proteome substrate phage libraries.  View on PubMed
  9. Zamecnik CR, Rajan JV, Yamauchi KA, Mann SA, Loudermilk RP, Sowa GM, Zorn KC, Alvarenga BD, Gaebler C, Caskey M, Stone M, Norris PJ, Gu W, Chiu CY, Ng D, Byrnes JR, Zhou XX, Wells JA, Robbiani DF, Nussenzweig MC, DeRisi JL, Wilson MR ReScan, a Multiplex Diagnostic Pipeline, Pans Human Sera for SARS-CoV-2 Antigens.  View on PubMed
  10. Byrnes JR, Zhou XX, Lui I, Elledge SK, Glasgow JE, Lim SA, Loudermilk RP, Chiu CY, Wang TT, Wilson MR, Leung KK, Wells JA Competitive SARS-CoV-2 Serology Reveals Most Antibodies Targeting the Spike Receptor-Binding Domain Compete for ACE2 Binding.  View on PubMed
  11. Elledge SK, Zhou XX, Byrnes JR, Martinko AJ, Lui I, Pance K, Lim SA, Glasgow JE, Glasgow AA, Turcios K, Iyer N, Torres L, Peluso MJ, Henrich TJ, Wang TT, Tato CM, Leung KK, Greenhouse B, Wells JA Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection.  View on PubMed
  12. Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, Zha BS, Schaefer K, Byrnes JR, Zhou J, Lui I, Liu J, Pance K, Zhou XX, Leung KK, Wells JA Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike.  View on PubMed
  13. Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Lim SA, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Zhou XX, Hobman TC, Kortemme T, Wells JA Engineered ACE2 receptor traps potently neutralize SARS-CoV-2.  View on PubMed
  14. Lim DC, Joukov V, Rettenmaier TJ, Kumagai A, Dunphy WG, Wells JA, Yaffe MB Redox priming promotes Aurora A activation during mitosis.  View on PubMed
  15. Lim SA, Wells JA Split enzymes: Design principles and strategy.  View on PubMed
  16. Byrnes JR, Zhou XX, Lui I, Elledge SK, Glasgow JE, Lim SA, Loudermilk R, Chiu CY, Wilson MR, Leung KK, Wells JA A SARS-CoV-2 serological assay to determine the presence of blocking antibodies that compete for human ACE2 binding.  View on PubMed
  17. Harvey EP, Hauseman ZJ, Cohen DT, Rettenmaier TJ, Lee S, Huhn AJ, Wales TE, Seo HS, Luccarelli J, Newman CE, Guerra RM, Bird GH, Dhe-Paganon S, Engen JR, Wells JA, Walensky LD Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.  View on PubMed
  18. Moroz A, Wang YH, Sharib JM, Wei J, Zhao N, Huang Y, Chen Z, Martinko AJ, Zhuo J, Lim SA, Zhang LH, Seo Y, Carlin S, Leung KK, Collisson EA, Kirkwood KS, Wells JA, Evans MJ Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer.  View on PubMed
  19. Kagan J, Moritz RL, Mazurchuk R, Lee JH, Kharchenko PV, Rozenblatt-Rosen O, Ruppin E, Edfors F, Ginty F, Goltsev Y, Wells JA, LaCava J, Riesterer JL, Germain RN, Shi T, Chee MS, Budnik BA, Yates JR, Chait BT, Moffitt JR, Smith RD, Srivastava S National Cancer Institute Think-Tank Meeting Report on Proteomic Cartography and Biomarkers at the Single-Cell Level: Interrogation of Premalignant Lesions.  View on PubMed
  20. Leung KK, Wilson GM, Kirkemo LL, Riley NM, Coon JJ, Wells JA Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes.  View on PubMed

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