William DeGrado explained

William F. DeGrado
Nationality:American
Birth Date:1955
Fields:Chemistry, Biochemistry and Biophysics
Known For:De novo protein design and small molecule drug discovery
Workplaces:University of California, San Francisco
Alma Mater:Kalamazoo College
University of Chicago

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.

Early life and 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) under the direction of Emil T. Kaiser, 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

External links

Notes and References

  1. Web site: Department of Pharmaceutical Chemistry . UCSF Department of Pharmaceutical Chemistry . January 10, 2017 . 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 . 10.1126/science.3043666 . 3043666 . 1988Sci...241..976R . 0036-8075.
  3. DeGrado . William F. . Wasserman . Zelda R. . Lear . James D. . February 3, 1989 . Protein Design, a Minimalist Approach . Science . 243 . 4891 . 622–628 . 10.1126/science.2464850 . 2464850 . 1989Sci...243..622D . 0036-8075.
  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 . 10.1126/science.270.5238.935 . 7481798 . 1995Sci...270..935B . 31116489 . 0036-8075.
  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 . 10.1073/pnas.96.10.5486 . 10318910 . 21886 . 1999PNAS...96.5486W . 0027-8424. free .
  6. Desjarlais . John R. . Handel . Tracy M. . 1995 . De novo design of the hydrophobic cores of proteins . Protein Science . 4 . 10 . 2006–2018 . 10.1002/pro.5560041006 . 8535237 . 2142989 . 0961-8368.
  7. Dahiyat . Bassil I. . Mayo . Stephen L. . 1996 . Protein design automation . Protein Science . 5 . 5 . 895–903 . 10.1002/pro.5560050511 . 8732761 . 2143401 . 0961-8368.
  8. Dahiyat . Bassil I. . Mayo . Stephen L. . October 3, 1997 . De Novo Protein Design: Fully Automated Sequence Selection . Science . 278 . 5335 . 82–87 . 10.1126/science.278.5335.82 . 9311930 . 0036-8075.
  9. Ponder . Jay W. . Richards . Frederic M. . 1987 . Tertiary templates for proteins . Journal of Molecular Biology . 193 . 4 . 775–791 . 10.1016/0022-2836(87)90358-5 . 2441069 . 0022-2836.
  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 . en . 349 . 6255 . 1504–1510 . 10.1126/science.aab1369 . 26404828 . 6260792 . 2015Sci...349.1504C . 0036-8075.
  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 . 10.1073/pnas.2136623100 . 14671331 . 307594 . 2003PNAS..10015486Z . 0027-8424. free .
  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 . en . 48 . 8 . 2388–2396 . 10.1021/acs.accounts.5b00175 . 26237119 . 5257248 . 0001-4842.
  13. Web site: Arcellx Cell Therapies for Cancer and Autoimmune Diseases . Arcellx . February 6, 2023 . 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 . en . 27 . 7 . 1262–1274 . 10.1016/j.ymthe.2019.04.010. 31043341 . 6612629 .
  15. Web site: Master Protocol for the Phase 1 Study of Cell Therapies in Multiple Myeloma - Full Text View . ClinicalTrials.gov . November 7, 2019 . February 8, 2023.
  16. Korendovych . Ivan V. . DeGrado . William F. . 2020 . De novo protein design, a retrospective . Quarterly Reviews of Biophysics . en . 53 . e3 . 10.1017/S0033583519000131 . 32041676 . 7243446 . 0033-5835.
  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 . 10.1021/cr000045i . 11710070 . 0009-2665.
  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 . en . 43 . 1 . 30–39 . 10.1021/ar900036b . 19813703 . 2808429 . 0001-4842.
  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 . 10.1021/ja953163+ . 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 . 10.1161/01.cir.93.3.537 . 8565173 . 0009-7322.
  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 . en . 7 . 288 . 288ra79 . 10.1126/scitranslmed.aaa5094 . 25995225 . 4461057 . 1946-6234.
  22. Web site: Pliant . Pliant . January 5, 2023 . February 8, 2023.
  23. Web site: The Protein Society : Protein Society Awards . The Protein Society . February 8, 2023.
  24. Web site: Recipients ACS Division of Biological Chemistry Website. www.divbiolchem.org. en-US. March 22, 2018.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "William DeGrado".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.