William DeGrado

William (Bill) DeGrado (born 1955) is a professor at the University of California, San Francisco, where he is the Toby Herfindal Presidential Professor of Entrepreneurship and Innovation in the Department of Pharmaceutical Chemistry.[1] As an early pioneer of protein design, he coined the term de novo protein design. He is also active in discovery of small molecule drugs for a variety of human diseases. He is a member of the U.S. National Academy of Sciences (1999), American Academy of Arts & Sciences (1997) and National Academy of Inventors. He also is a scientific cofounder of Pliant therapeutics.

William F. DeGrado
Born1955
NationalityAmerican
Alma materUniversity of Chicago
Known forDe novo protein design and small molecule drug discovery
Scientific career
FieldsChemistry, Biochemistry and Biophysics
InstitutionsUniversity of California, San Francisco

Early life & Education

Following high school graduation, DeGrado worked in a coat rack factory, an experience that motivated him to further his education. He attended colleges in the Chicago suburbs, while running a lawn-mowing service. About this time, his father, Jim DeGrado, designed the highly successful Red Solo Cup, while working as a commercial artist at Solo. In appreciation, Solo Cup offered DeGrado, a scholarship for the final two years of college, which DeGrado completed at Kalamazoo College.

DeGrado received his B.A. in chemistry from Kalamazoo College (1978) and a doctorate in organic chemistry from the University of Chicago (1981).

Industrial and academic career

After receiving his PhD in organic chemistry from the University of Chicago (1981), DeGrado began work at DuPont as a research chemist, eventually becoming a senior director for small molecule therapeutics in DuPont Merck's medicinal chemistry department. In 1995 he moved to the University of Pennsylvania, where he was a professor in the biochemistry and biophysics department as well as an adjunct professor in the department of chemistry. Since 2011 he has been at the University of California, San Francisco School of Pharmacy, where he is the Toby Herfindal Presidential Professor of Entrepreneurship and Innovation. He is also a member of the Cardiovascular Research Institute and an adjunct member of the Institute for Neurodegenerative Diseases at UCSF.

Research

Starting in the 1980's DeGrado's group developed the approach of de novo protein design, a term they coined to describe the design of proteins from first principles rather than through modification of natural protein sequences.[2][3][4] They pioneered parametric approaches to the design of water-soluble 4-helix (alpha4) and 3-helix bundles (alpha3D), and ion channel peptides. The protein, alpha3D, was notable at the time, because it was the premier example of a de novo protein, which was biologically expressed, structurally validated, and whose sequence and structure were not based on the sequence or the precise tertiary structure of a natural protein.[5] The sequence of alpha3D was designed using the computational sidechain repacking algorithms that had recently been developed by Ponders & Richards,[6][7][8][9] Desjarlais & Handel, Dahiyat & Mayo. The folding kinetics of alpha3D are among the most extensively characterized of single-domain proteins,[10][11] and it has been used as a template for design of metalloproteins.[12] The company Arcellex[13] used alpha3D[14] as a starting point for design of chimeric antigen receptors (CARs). Clinical data announced in 2020 showed deep and durable responses of multiple myeloma, illustrating the potential of de novo proteins for treatment of human disease.[15]

With Angela Lombardi (University of Naples), Les Dutton and Michael Therien (Duke University) DeGrado has also designed numerous proteins that mimic many of the catalytic and electron relay properties of heme and non-heme iron proteins, including a transmembrane protein capable of shuttling electrons across membranes.[16] His group has also designed the first examples of de novo ion and proton channels.

Because the original approaches to de novo protein design focused on physical chemical principles it was easily extended to design biologically active polymers and foldamers (short homogeneous, sequence-specific polymers that fold into unique structures).[17] This work led to the design of Brilacidin,[18] which is currently in phase II clinical trials.

Contributions to Pharmaceutical Chemistry

DeGrado contributed significantly to the development of Brilacidin, which is in clinical trials for several indications. DeGrado's group also has contributed to the development of small molecule antagonists of integrins[19] that reached clinical trials.[20] His work on this subject with Dean Sheppard[21] also formed the basis for founding Pliant Pharmaceuticals,[22] a company conducting clinical trials on idiopathic pulmonary fibrosis (IPF) and primary sclerosing cholangitis.

Awards
  • 1988 Du Vigneaud Award for Young Investigators in Peptide Research
  • 1989 Protein Society Young Investigator Award
  • 1992 Eli Lilly Award in Biological Chemistry
  • 1993 DuPont Merck Summit Award
  • 1995 Fellow, American Association for the Advancement of Science
  • 1998 Fellow, AAAS
  • 1999 Member, National Academy of Sciences (U.S.A.)
  • 2003 The American Peptide Society Merrifield Award
  • 2008 The American Chemical Society Ralph F. Hirschmann Award in Peptide Chemistry
  • 2009 The American Peptide Society Makineni Award
  • 2015 The Stein & Moore Award of the Protein Society[23]
  • 2016 Weizmann Institute Max Perutz Memorial Lecture
  • 2018 The American Chemical Society Cope Scholar Award
  • 2018 The American Chemical Society Murray Goodman Memorial Prize[24]
  • 2020 The Franklin Institute & City Council of Philadelphia John C. Scott Award

References
  1. "Department of Pharmaceutical Chemistry". UCSF Department of Pharmaceutical Chemistry. January 10, 2017. Retrieved February 8, 2023.
  2. Regan, Lynne; DeGrado, William F. (August 19, 1988). "Characterization of a Helical Protein Designed from First Principles". Science. 241 (4868): 976–978. Bibcode:1988Sci...241..976R. doi:10.1126/science.3043666. ISSN 0036-8075. PMID 3043666.
  3. DeGrado, William F.; Wasserman, Zelda R.; Lear, James D. (February 3, 1989). "Protein Design, a Minimalist Approach". Science. 243 (4891): 622–628. Bibcode:1989Sci...243..622D. doi:10.1126/science.2464850. ISSN 0036-8075. PMID 2464850.
  4. Bryson, James W.; Betz, Stephen F.; Lu, Helen S.; Suich, Daniel J.; Zhou, Hongxing X.; O'Neil, Karyn T.; DeGrado, William F. (November 10, 1995). "Protein Design: A Hierarchic Approach". Science. 270 (5238): 935–941. Bibcode:1995Sci...270..935B. doi:10.1126/science.270.5238.935. ISSN 0036-8075. PMID 7481798. S2CID 31116489.
  5. Walsh, Scott T. R.; Cheng, Hong; Bryson, James W.; Roder, Heinrich; DeGrado, William F. (May 11, 1999). "Solution structure and dynamics of a de novo designed three-helix bundle protein". Proceedings of the National Academy of Sciences. 96 (10): 5486–5491. Bibcode:1999PNAS...96.5486W. doi:10.1073/pnas.96.10.5486. ISSN 0027-8424. PMC 21886. PMID 10318910.
  6. Desjarlais, John R.; Handel, Tracy M. (1995). "De novo design of the hydrophobic cores of proteins". Protein Science. 4 (10): 2006–2018. doi:10.1002/pro.5560041006. ISSN 0961-8368. PMC 2142989. PMID 8535237.
  7. Dahiyat, Bassil I.; Mayo, Stephen L. (1996). "Protein design automation". Protein Science. 5 (5): 895–903. doi:10.1002/pro.5560050511. ISSN 0961-8368. PMC 2143401. PMID 8732761.
  8. Dahiyat, Bassil I.; Mayo, Stephen L. (October 3, 1997). "De Novo Protein Design: Fully Automated Sequence Selection". Science. 278 (5335): 82–87. doi:10.1126/science.278.5335.82. ISSN 0036-8075. PMID 9311930.
  9. Ponder, Jay W.; Richards, Frederic M. (1987). "Tertiary templates for proteins". Journal of Molecular Biology. 193 (4): 775–791. doi:10.1016/0022-2836(87)90358-5. ISSN 0022-2836. PMID 2441069.
  10. Chung, Hoi Sung; Piana-Agostinetti, Stefano; Shaw, David E.; Eaton, William A. (September 25, 2015). "Structural origin of slow diffusion in protein folding". Science. 349 (6255): 1504–1510. Bibcode:2015Sci...349.1504C. doi:10.1126/science.aab1369. ISSN 0036-8075. PMC 6260792. PMID 26404828.
  11. Zhu, Yongjin; Alonso, Darwin O. V.; Maki, Kosuke; Huang, Cheng-Yen; Lahr, Steven J.; Daggett, Valerie; Roder, Heinrich; DeGrado, William F.; Gai, Feng (December 11, 2003). "Ultrafast folding of α3D: A de novo designed three-helix bundle protein". Proceedings of the National Academy of Sciences. 100 (26): 15486–15491. Bibcode:2003PNAS..10015486Z. doi:10.1073/pnas.2136623100. ISSN 0027-8424. PMC 307594. PMID 14671331.
  12. Mocny, Catherine S.; Pecoraro, Vincent L. (August 18, 2015). "De Novo Protein Design as a Methodology for Synthetic Bioinorganic Chemistry". Accounts of Chemical Research. 48 (8): 2388–2396. doi:10.1021/acs.accounts.5b00175. ISSN 0001-4842. PMC 5257248. PMID 26237119.
  13. "Arcellx Cell Therapies for Cancer and Autoimmune Diseases". Arcellx. February 6, 2023. Retrieved February 8, 2023.
  14. Qin, Haiying; Edwards, Justin P.; Zaritskaya, Liubov; Gupta, Ankit; Mu, C. Jenny; Fry, Terry J.; Hilbert, David M.; LaFleur, David W. (2019). "Chimeric Antigen Receptors Incorporating D Domains Targeting CD123 Direct Potent Mono- and Bi-specific Antitumor Activity of T Cells". Molecular Therapy. 27 (7): 1262–1274. doi:10.1016/j.ymthe.2019.04.010. PMC 6612629. PMID 31043341.
  15. "Master Protocol for the Phase 1 Study of Cell Therapies in Multiple Myeloma - Full Text View". ClinicalTrials.gov. November 7, 2019. Retrieved February 8, 2023.
  16. Korendovych, Ivan V.; DeGrado, William F. (2020). "De novo protein design, a retrospective". Quarterly Reviews of Biophysics. 53: e3. doi:10.1017/S0033583519000131. ISSN 0033-5835. PMC 7243446. PMID 32041676.
  17. Cheng, Richard P.; Gellman, Samuel H.; DeGrado, William F. (October 1, 2001). "β-Peptides: From Structure to Function". Chemical Reviews. 101 (10): 3219–3232. doi:10.1021/cr000045i. ISSN 0009-2665. PMID 11710070.
  18. Tew, Gregory N.; Scott, Richard W.; Klein, Michael L.; DeGrado, William F. (January 19, 2010). "De Novo Design of Antimicrobial Polymers, Foldamers, and Small Molecules: From Discovery to Practical Applications". Accounts of Chemical Research. 43 (1): 30–39. doi:10.1021/ar900036b. ISSN 0001-4842. PMC 2808429. PMID 19813703.
  19. Bach, Alvin C.; Espina, J. Robert; Jackson, Sharon A.; Stouten, Pieter F. W.; Duke, Jodie L.; Mousa, Shaker A.; DeGrado, William F. (January 1, 1996). "Type II' to Type I β-Turn Swap Changes Specificity for Integrins". Journal of the American Chemical Society. 118 (1): 293–294. doi:10.1021/ja953163+. ISSN 0002-7863.
  20. Mousa, Shaker A.; DeGrado, William F.; Mu, Dun-Xu; Kapil, Ram P.; Lucchesi, Benedict R.; Reilly, Thomas M. (1996). "Oral Antiplatelet, Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Antagonist". Circulation. 93 (3): 537–543. doi:10.1161/01.cir.93.3.537. ISSN 0009-7322. PMID 8565173.
  21. Reed, Nilgun I.; Jo, Hyunil; Chen, Chun; Tsujino, Kazuyuki; Arnold, Thomas D.; DeGrado, William F.; Sheppard, Dean (May 20, 2015). "The α v β 1 integrin plays a critical in vivo role in tissue fibrosis". Science Translational Medicine. 7 (288): 288ra79. doi:10.1126/scitranslmed.aaa5094. ISSN 1946-6234. PMC 4461057. PMID 25995225.
  22. "Pliant". Pliant. January 5, 2023. Retrieved February 8, 2023.
  23. "The Protein Society : Protein Society Awards". The Protein Society. Retrieved February 8, 2023.
  24. "Recipients | ACS Division of Biological Chemistry Website". www.divbiolchem.org. Retrieved March 22, 2018.
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