Paul Negulescu Explained

Paul Negulescu
Birth Name:Paul Adrian Negulescu[1]
Birth Place:San Francisco[2]
Fields:Cell biology
Workplaces:University of California, Irvine
Aurora Biosciences
Vertex Pharmaceuticals
Education:University of California, Berkeley (BSc, PhD)
Doctoral Advisor:Terry Machen
Thesis Title:The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell
Thesis Year:1988
Thesis Url:https://search.library.berkeley.edu/permalink/01UCS_BER/s4lks2/cdi_proquest_journals_303683972
Known For:Research of cystic fibrosis
Awards:Warren Alpert Foundation Prize (2018)
Shaw Prize in Life Science & Medicine (2022)
Wiley Prize (2023)
Breakthrough Prize in Life Sciences (2024)

Paul Adrian Negulescu is an American–Romanian cell biologist. He is a Senior Vice President at American pharmaceutical company Vertex Pharmaceuticals. He received the 2022 Shaw Prize in Life science and medicine, together with Michael J. Welsh, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.[3]

Early life and education

Negulescu was born in San Francisco to first-generation immigrants from Romania. His father was a surgeon,[2] and his grandfather, Constantin Vișoianu, was a former Minister of Foreign Affairs of Romania.[4] [5] He has a brother.[2]

Thanks to his childhood experience, he initially wanted to graduate with history from the University of California, Berkeley. A third-year physiology class taught by Roger Y. Tsien had a great influence on Negulescu, who eventually graduated with a dual degree in history and physiology in 1986. He then went on and studied PhD in physiology under Terry Machen, completing it in 1990.[2]

Career

Negulescu started his career as a postdoctoral researcher at the University of California, Berkeley and under Michael Cahalan at the University of California, Irvine. He was planning to move to the University of Connecticut when Roger Y. Tsien asked him to join a startup company he was forming called Aurora Biosciences.[2] [6] Negulescu joined Aurora Biosciences in 1996 as one of the first employees.[7] He became Senior Vice President of Discovery Biology in 1999. When Vertex Pharmaceuticals acquired Aurora Biosciences in 2001,[8] he was appointed Senior Vice President of Research.[2] Negulescu has been leading the San Diego Research Center of Vertex Pharmaceuticals since 2003.[9]

Research

Negulescu's research focuses on the therapy of cystic fibrosis. Cystic fibrosis can be caused by any of the thousands of identified mutations in the CFTR protein, an ion channel that allows chloride ions to pass through. These mutations have been classified into Class I to V, with Class III mutations causing defective channel gates in CFTR despite normal expression of the protein.[10] Via high-throughput screening, his team at Vertex Pharmaceuticals discovered ivacaftor, a small-molecule potentiator that increases the probability that mutated CFTR gates will open.[11] [12] Ivacaftor was approved by the Food and Drug Administration (FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well.[13] Of note, the expanded approval in 2017 was based solely on in vitro data, due to the small number of patients carrying those rare mutations making clinical trials impossible.[14]

Negulescu also led the discovery of another cystic fibrosis drug, lumacaftor, which is known as a "corrector" as it acts as a chaperone to help the CFTR protein fold correctly.[15] Thus, it can be used in patients with Class II mutations, which create misfolded CFTR protein that cannot reaching the cell surface.[13] The most common Class II mutation is F508del.[16] Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein.[17] It was later found that the drug was not effective enough when administered on its own,[18] but was so when administered together with ivacaftor.[19] The FDA approved this drug combination in 2015.[20] Further research led to the discovery of tezacaftor and elexacaftor, 2 other correctors of the CFTR protein.[21] The triple combination elexacaftor/tezacaftor/ivacaftor was approved by the FDA in 2019.[22]

Honors and awards

Personal life

Negulescu met his wife, Debbie, during his time at the University of California, Irvine.[2]

Notes and References

  1. Web site: The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell . . October 12, 2022 . https://web.archive.org/web/20221012135153/https://search.library.berkeley.edu/discovery/fulldisplay?context=PC&vid=01UCS_BER:UCB&search_scope=DN_and_CI&tab=Default_UCLibrarySearch&docid=cdi_proquest_journals_303683972 . October 12, 2022.
  2. Web site: Autobiography of Paul A Negulescu . . October 12, 2022 . https://web.archive.org/web/20221012065843/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/autobiography-of-paul-a-negulescu . October 12, 2022.
  3. Press Release . October 12, 2022 . Shaw Prize Foundation . May 24, 2022 . https://web.archive.org/web/20221012140007/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/press-relesae . October 12, 2022.
  4. News: Florica Visoianu Obituary . October 15, 2022 . . April 10, 2005 . https://web.archive.org/web/20221015155707/https://www.legacy.com/us/obituaries/washingtonpost/name/florica-visoianu-obituary?id=5528520 . October 15, 2022.
  5. News: Constantin Vișoianu, Romanian official, dies . October 15, 2022 . The Washington Post . January 5, 1994 . https://web.archive.org/web/20221015160905/https://www.washingtonpost.com/archive/local/1994/01/05/constantin-visoianu-96-romanian-official-dies/db81322d-4afd-4e22-99ef-37cb4f107228/ . October 15, 2022.
  6. Kresge . Nicole . Simoni . Robert D. . Hill . Robert L. . The Chemistry of Fluorescent Indicators: the Work of Roger Y. Tsien . . 2006 . 281 . 37 . e29–e31 . 10.1016/S0021-9258(19)34942-7 . October 15, 2022 . October 15, 2022 . https://web.archive.org/web/20221015163531/https://www.jbc.org/article/S0021-9258%2819%2934942-7/fulltext. free .
  7. Web site: Paul Negulescu . . October 15, 2022 . https://web.archive.org/web/20221015164423/https://warrenalpert.org/prize-recipients/paul-negulescu . October 15, 2022.
  8. News: Pollack . Andrew . TECHNOLOGY; Vertex Buys Biotechnology Rival for $592 Million . October 16, 2022 . . May 1, 2001 . https://web.archive.org/web/20221016144750/https://www.nytimes.com/2001/05/01/business/technology-vertex-buys-biotechnology-rival-for-592-million.html . October 16, 2022.
  9. Web site: Paul Negulescu, Ph.D. . . May 8, 2019 . https://web.archive.org/web/20190508110513/https://www.vrtx.com/leadership/paul-negulescu-phd . May 8, 2019.
  10. Michal . Shteinberg . Iram J . Haq . Deepika . Polineni . Jane C . Davies . Cystic fibrosis . . 2021 . 397 . 10290 . 2195–2211 . 10.1016/S0140-6736(20)32542-3 . 34090606 . 235327978 . October 17, 2022.
  11. Fredrick . Van Goor . Sabine . Hadida . Peter D. J. . Grootenhuis . Bill . Burton . Dong . Cao . Tim . Neuberger . Amanda . Turnbull . Ashvani . Singh . John . Joubran . Anna . Hazlewood . Jinglan . Zhou . Jason . McCartney . Vijayalaksmi . Arumugam . Caroline . Decker . Jennifer . Yang . Chris . Young . Eric R. . Olson . Jeffery J. . Wine . Raymond A. . Frizzell . Melissa . Ashlock . Paul . Negulescu . Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 . . 2009 . 106 . 44 . 18825–18830 . 10.1073/pnas.0904709106 . 19846789 . 2773991. 2009PNAS..10618825V . free .
  12. Lawrence . Lin . Sook Wah . Yee . Richard B. . Kim . Kathleen M. . Giacomini . SLC transporters as therapeutic targets: emerging opportunities . . 2015 . 14 . 8 . 543–560 . 10.1038/nrd4626 . 26111766 . 4698371 .
  13. Michael M. . Rey . Michael P. . Bonk . Denis . Hadjiliadis . Cystic Fibrosis: Emerging Understanding and Therapies . . 2019 . 70 . 197–210 . 10.1146/annurev-med-112717-094536 . 30312551 . 52975540 . October 17, 2022. free .
  14. Kingwell . Katie . FDA OKs first in vitro route to expanded approval . Nature Reviews Drug Discovery . 2017 . 16 . 9 . 591–592 . 10.1038/nrd.2017.140 . 28860581 . 2421594 . October 17, 2022.
  15. Fiedorczuk . Karol . Chen . Jue . Mechanism of CFTR correction by type I folding correctors . . 2022 . 185 . 1 . 158–168 . 10.1016/j.cell.2021.12.009 . 34995514 . 235649986 . free .
  16. Web site: Types of CFTR Mutations . . October 18, 2022 . https://web.archive.org/web/20221018143639/https://www.cff.org/research-clinical-trials/types-cftr-mutations . October 18, 2022.
  17. Fredrick . Van Goor . Sabine . Hadida . Peter D. J. . Grootenhuis . Bill . Burton . Jeffrey H. . Stack . Kimberly S. . Straley . Caroline J. . Decker . Mark . Miller . Jason . McCartney . Eric R. . Olson . Jeffrey J. . Wine . Ray A. . Frizzell . Melissa . Ashlock . Paul A. . Negulescu . Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 . Proceedings of the National Academy of Sciences . 2011 . 108 . 46 . 18843–18848 . 10.1073/pnas.1105787108 . 21976485 . 3219147 . 2011PNAS..10818843V . free .
  18. J. P. . Clancy . Steven M. . Rowe . Frank J. . Accurso . Moira L. . Aitken . Raouf S. . Amin . Melissa A. . Ashlock . Manfred . Ballmann . Michael P. . Boyle . Inez . Bronsveld . Preston W. . Campbell . Kris . De Boeck . Scott H. . Donaldson . Henry L. . Dorkin . Jordan M. . Dunitz . Peter R. . Durie . Manu . Jain . Anissa . Leonard . Karen S. . McCoy . Richard B. . Moss . Joseph M. . Pilewski . Daniel B. . Rosenbluth . Ronald C. . Rubenstein . Michael S. . Schechter . Martyn . Botfield . Claudia L . Ordoñez . George T. . Spencer-Green . Laurent . Vernillet . Steve . Wisseh . Karl . Yen . Michael W. . Konstan . Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation . . 2012 . 67 . 1 . 12–18 . 10.1136/thoraxjnl-2011-200393 . 21825083 . October 19, 2022 . 3746507 . October 19, 2022 . https://archive.today/20221019031143/https://thorax.bmj.com/content/67/1/12.
  19. Claire E. . Wainwright . J. Stuart . Elborn . Bonnie W. . Ramsey . Gautham . Marigowda . Xiaohong . Huang . Marco . Cipolli . Carla . Colombo . Jane C. . Davies . Kris . De Boeck . Patrick A. . Flume . Michael W. . Konstan . Susanna A. . McColley . Karen . McCoy . Edward F. . McKone . Anne . Munck . Felix . Ratjen . Steven M. . Rowe . David . Waltz . Michael P. . Boyle . TRAFFIC Study Group . TRANSPORT Study Group . Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR . . 2015 . 373 . 3 . 220–231 . 10.1056/NEJMoa1409547 . 25981758 . 4764353 .
  20. News: Morgan . David . FDA panel recommends Vertex cystic fibrosis treatment . October 19, 2022 . . May 13, 2015 . https://web.archive.org/web/20221019071722/https://www.reuters.com/article/us-vertex-fda-recommendation-idUSKBN0NX2EH20150512 . October 19, 2022.
  21. Web site: Essay . Shaw Prize Foundation . October 18, 2022 . https://web.archive.org/web/20221012140641/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/essay . October 12, 2022 . September 29, 2022.
  22. FDA approves new breakthrough therapy for cystic fibrosis . October 20, 2022 . . October 21, 2019 . https://web.archive.org/web/20221020072702/https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis . October 20, 2022.
  23. Web site: The 2022 Prize in Life Science & Medicine . Shaw Prize Foundation . 5 October 2022 . https://web.archive.org/web/20221005032240/https://www.shawprize.org/laureates/life-science-medicine/2022 . 5 October 2022.
  24. http://johnwiley2020news.q4web.com/press-releases/press-release-details/2023/-The-21st-Annual-Wiley-Prize-in-Biomedical-Sciences-Awarded-for-Novel-Cystic-Fibrosis-Treatment/default.aspx Wiley Prize 2023
  25. Web site: September 14, 2023 . BREAKTHROUGH PRIZE ANNOUNCES 2024 LAUREATES IN LIFE SCIENCES, FUNDAMENTAL PHYSICS, AND MATHEMATICS . September 14, 2023 . BREAKTHROUGH PRIZE.

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