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. Cotton AD, Wells JA, Seiple IB. Biotin as a Reactive Handle to Selectively Label Proteins and DNA with Small Molecules. ACS Chem Biol. 2021 Aug 19.  View on PubMed
  2. Kang E, Kadoch C, Rubenstein JL, Lanier LL, Wells JA. A functional mammalian display screen identifies rare antibodies that stimulate NK cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2021 Aug 03; 118(31).  View on PubMed
  3. Peluso MJ, Takahashi S, Hakim J, Kelly JD, Torres L, Iyer NS, Turcios K, Janson O, Munter SE, Thanh C, Donatelli J, Nixon CC, Hoh R, Tai V, Fehrman EA, Hernandez Y, Spinelli MA, Gandhi M, Palafox MA, Vallari A, Rodgers MA, Prostko J, Hackett J, Trinh L, Wrin T, Petropoulos CJ, Chiu CY, Norris PJ, DiGermanio C, Stone M, Busch MP, Elledge SK, Zhou XX, Wells JA, Shu A, Kurtz TW, Pak JE, Wu W, Burbelo PD, Cohen JI, Rutishauser RL, Martin JN, Deeks SG, Henrich TJ, Rodriguez-Barraquer I, Greenhouse B. SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay. Sci Adv. 2021 Jul; 7(31).  View on PubMed
  4. Gallo E, Kelil A, Haughey M, Cazares-Olivera M, Yates BP, Zhang M, Wang NY, Blazer L, Carderelli L, Adams JJ, Kossiakoff AA, Wells JA, Xie W, Sidhu SS. Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on av Integrins. J Mol Biol. 2021 Jul 23; 433(15):167090.  View on PubMed
  5. Glasgow J, Glasgow A, Kortemme T, Wells JA. Reply to Liu et al.: Specific mutations matter in specificity and catalysis in ACE2. Proc Natl Acad Sci U S A. 2021 Apr 13; 118(15).  View on PubMed
  6. Elledge SK, Zhou XX, Byrnes JR, Martinko AJ, Lui I, Pance K, Lim SA, Glasgow JE, Glasgow AA, Turcios K, Iyer NS, 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. Nat Biotechnol. 2021 08; 39(8):928-935.  View on PubMed
  7. Muller YD, Nguyen DP, Ferreira LMR, Ho P, Raffin C, Valencia RVB, Congrave-Wilson Z, Roth TL, Eyquem J, Van Gool F, Marson A, Perez L, Wells JA, Bluestone JA, Tang Q. The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Front Immunol. 2021; 12:639818.  View on PubMed
  8. Peluso MJ, Takahashi S, Hakim J, Kelly JD, Torres L, Iyer NS, Turcios K, Janson O, Munter SE, Thanh C, Nixon CC, Hoh R, Tai V, Fehrman EA, Hernandez Y, Spinelli MA, Gandhi M, Palafox MA, Vallari A, Rodgers MA, Prostko J, Hackett J, Trinh L, Wrin T, Petroplolous CJ, Chiu CY, Norris PJ, DiGermanio C, Stone M, Busch MP, Elledge SK, Zhou XX, Wells JA, Shu A, Kurtz TW, Pak JE, Wu W, Burbelo PD, Cohen JI, Rutishauser RL, Martin JN, Deeks SG, Henrich TJ, Rodriguez-Barraquer I, Greenhouse B. SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay. medRxiv. 2021 Mar 05.  View on PubMed
  9. Weeks AM, Byrnes JR, Lui I, Wells JA. Mapping proteolytic neo-N termini at the surface of living cells. Proc Natl Acad Sci U S A. 2021 02 23; 118(8).  View on PubMed
  10. Santarelli A, Lalitsasivimol D, Bartholomew N, Reid S, Reid J, Lyon C, Wells J, Ashurst J. The seroprevalence of SARS-CoV-2 in a rural southwest community. J Osteopath Med. 2021 Feb 01; 121(2):199-210.  View on PubMed
  11. 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. Proc Natl Acad Sci U S A. 2021 01 26; 118(4).  View on PubMed
  12. 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. bioRxiv. 2021 Jan 19.  View on PubMed
  13. 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. J Am Chem Soc. 2021 01 20; 143(2):593-598.  View on PubMed
  14. Lim SA, Gramespacher JA, Pance K, Rettko NJ, Solomon P, Jin J, Lui I, Elledge SK, Liu J, Bracken CJ, Simmons G, Zhou XX, Leung KK, Wells JA. Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2. MAbs. 2021 Jan-Dec; 13(1):1893426.  View on PubMed
  15. 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. Proc Natl Acad Sci U S A. 2020 11 10; 117(45):28046-28055.  View on PubMed
  16. Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, Zha BS, Schaefer K, Byrnes JR, Zhou J, Lui I, Liu J, Pance K, QCRG Structural Biology Consortium , Zhou XX, Leung KK, Wells JA. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2. Nat Chem Biol. 2021 01; 17(1):113-121.  View on PubMed
  17. 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. J Am Chem Soc. 2020 10 14; 142(41):17703-17713.  View on PubMed
  18. 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. Proc Natl Acad Sci U S A. 2020 10 13; 117(41):25464-25475.  View on PubMed
  19. 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. Cell Rep Med. 2020 Oct 20; 1(7):100123.  View on PubMed
  20. 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. mSphere. 2020 09 16; 5(5).  View on PubMed

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