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Paul Negulescu

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Paul Negulescu
Born
Paul Adrian Negulescu[2]

San Francisco[1]
EducationUniversity of California, Berkeley (BSc, PhD)[1]
Known forResearch of cystic fibrosis
AwardsWarren Alpert Foundation Prize (2018)
Shaw Prize in Life Science & Medicine (2022)
Wiley Prize (2023)
Breakthrough Prize in Life Sciences (2024)
Scientific career
FieldsCell biology
InstitutionsUniversity of California, Irvine
Aurora Biosciences
Vertex Pharmaceuticals[1]
ThesisThe role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell (1988)
Doctoral advisorTerry Machen[1]

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

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Negulescu was born in San Francisco to first-generation immigrants from Romania. His father was a surgeon,[1] and his grandfather, Constantin Vișoianu, was a former Minister of Foreign Affairs of Romania.[4][5] He has a brother.[1]

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.[1]

Career

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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.[1][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.[1] Negulescu has been leading the San Diego Research Center of Vertex Pharmaceuticals since 2003.[9]

Research

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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

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Personal life

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Negulescu met his wife, Debbie, during his time at the University of California, Irvine.[1]

References

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  1. ^ a b c d e f g h i j "Autobiography of Paul A Negulescu". Shaw Prize Foundation. Archived from the original on October 12, 2022. Retrieved October 12, 2022.
  2. ^ "The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell". University of California, Berkeley. Archived from the original on October 12, 2022. Retrieved October 12, 2022.
  3. ^ "Press Release" (Press release). Shaw Prize Foundation. May 24, 2022. Archived from the original on October 12, 2022. Retrieved October 12, 2022.
  4. ^ "Florica Visoianu Obituary". The Washington Post. April 10, 2005. Archived from the original on October 15, 2022. Retrieved October 15, 2022.
  5. ^ "Constantin Vișoianu, Romanian official, dies". The Washington Post. January 5, 1994. Archived from the original on October 15, 2022. Retrieved October 15, 2022.
  6. ^ Kresge, Nicole; Simoni, Robert D.; Hill, Robert L. (2006). "The Chemistry of Fluorescent Indicators: the Work of Roger Y. Tsien". Journal of Biological Chemistry. 281 (37): e29–e31. doi:10.1016/S0021-9258(19)34942-7. Archived from the original on October 15, 2022. Retrieved October 15, 2022.
  7. ^ a b "Paul Negulescu". Warren Alpert Foundation. Archived from the original on October 15, 2022. Retrieved October 15, 2022.
  8. ^ Pollack, Andrew (May 1, 2001). "TECHNOLOGY; Vertex Buys Biotechnology Rival for $592 Million". The New York Times. Archived from the original on October 16, 2022. Retrieved October 16, 2022.
  9. ^ "Paul Negulescu, Ph.D." Vertex Pharmaceuticals. Archived from the original on May 8, 2019. Retrieved May 8, 2019.
  10. ^ Shteinberg, Michal; Haq, Iram J; Polineni, Deepika; Davies, Jane C (2021). "Cystic fibrosis". The Lancet. 397 (10290): 2195–2211. doi:10.1016/S0140-6736(20)32542-3. PMID 34090606. S2CID 235327978. Retrieved October 17, 2022.
  11. ^ Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Cao, Dong; Neuberger, Tim; Turnbull, Amanda; Singh, Ashvani; Joubran, John; Hazlewood, Anna; Zhou, Jinglan; McCartney, Jason; Arumugam, Vijayalaksmi; Decker, Caroline; Yang, Jennifer; Young, Chris; Olson, Eric R.; Wine, Jeffery J.; Frizzell, Raymond A. (2009). "Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770". Proceedings of the National Academy of Sciences. 106 (44): 18825–18830. Bibcode:2009PNAS..10618825V. doi:10.1073/pnas.0904709106. PMC 2773991. PMID 19846789.
  12. ^ Lin, Lawrence; Yee, Sook Wah; Kim, Richard B.; Giacomini, Kathleen M. (2015). "SLC transporters as therapeutic targets: emerging opportunities". Nature Reviews Drug Discovery. 14 (8): 543–560. doi:10.1038/nrd4626. PMC 4698371. PMID 26111766.
  13. ^ a b Rey, Michael M.; Bonk, Michael P.; Hadjiliadis, Denis (2019). "Cystic Fibrosis: Emerging Understanding and Therapies". Annual Review of Medicine. 70: 197–210. doi:10.1146/annurev-med-112717-094536. PMID 30312551. S2CID 52975540. Retrieved October 17, 2022.
  14. ^ Kingwell, Katie (2017). "FDA OKs first in vitro route to expanded approval". Nature Reviews Drug Discovery. 16 (9): 591–592. doi:10.1038/nrd.2017.140. PMID 28860581. S2CID 2421594. Retrieved October 17, 2022.
  15. ^ Fiedorczuk, Karol; Chen, Jue (2022). "Mechanism of CFTR correction by type I folding correctors". Cell. 185 (1): 158–168. doi:10.1016/j.cell.2021.12.009. PMID 34995514. S2CID 235649986.
  16. ^ "Types of CFTR Mutations". Cystic Fibrosis Foundation. Archived from the original on October 18, 2022. Retrieved October 18, 2022.
  17. ^ Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A. (2011). "Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809". Proceedings of the National Academy of Sciences. 108 (46): 18843–18848. Bibcode:2011PNAS..10818843V. doi:10.1073/pnas.1105787108. PMC 3219147. PMID 21976485.
  18. ^ Clancy, J. P.; Rowe, Steven M.; Accurso, Frank J.; Aitken, Moira L.; Amin, Raouf S.; Ashlock, Melissa A.; Ballmann, Manfred; Boyle, Michael P.; Bronsveld, Inez; Campbell, Preston W.; De Boeck, Kris; Donaldson, Scott H.; Dorkin, Henry L.; Dunitz, Jordan M.; Durie, Peter R.; Jain, Manu; Leonard, Anissa; McCoy, Karen S.; Moss, Richard B.; Pilewski, Joseph M.; Rosenbluth, Daniel B.; Rubenstein, Ronald C.; Schechter, Michael S.; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T.; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W. (2012). "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". Thorax. 67 (1): 12–18. doi:10.1136/thoraxjnl-2011-200393. PMC 3746507. PMID 21825083. Archived from the original on October 19, 2022. Retrieved October 19, 2022.
  19. ^ Wainwright, Claire E.; Elborn, J. Stuart; Ramsey, Bonnie W.; Marigowda, Gautham; Huang, Xiaohong; Cipolli, Marco; Colombo, Carla; Davies, Jane C.; De Boeck, Kris; Flume, Patrick A.; Konstan, Michael W.; McColley, Susanna A.; McCoy, Karen; McKone, Edward F.; Munck, Anne; Ratjen, Felix; Rowe, Steven M.; Waltz, David; Boyle, Michael P.; TRAFFIC Study Group; TRANSPORT Study Group (2015). "Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR". The New England Journal of Medicine. 373 (3): 220–231. doi:10.1056/NEJMoa1409547. PMC 4764353. PMID 25981758.
  20. ^ Morgan, David (May 13, 2015). "FDA panel recommends Vertex cystic fibrosis treatment". Reuters. Archived from the original on October 19, 2022. Retrieved October 19, 2022.
  21. ^ "Essay". Shaw Prize Foundation. September 29, 2022. Archived from the original on October 12, 2022. Retrieved October 18, 2022.
  22. ^ "FDA approves new breakthrough therapy for cystic fibrosis" (Press release). Food and Drug Administration. October 21, 2019. Archived from the original on October 20, 2022. Retrieved October 20, 2022.
  23. ^ "The 2022 Prize in Life Science & Medicine". Shaw Prize Foundation. Archived from the original on October 5, 2022. Retrieved October 5, 2022.
  24. ^ Wiley Prize 2023
  25. ^ "BREAKTHROUGH PRIZE ANNOUNCES 2024 LAUREATES IN LIFE SCIENCES, FUNDAMENTAL PHYSICS, AND MATHEMATICS". BREAKTHROUGH PRIZE. September 14, 2023. Retrieved September 14, 2023.
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