Paul Adrian Negulescu is an American–Romaniancell biologist. He is a Senior Vice President at Americanpharmaceutical companyVertex Pharmaceuticals. He received the 2022Shaw Prize in Life science and medicine, together withMichael J. Welsh, for their work that uncovered theetiology ofcystic fibrosis and developed effectivemedications.^[3]

Negulescu was born inSan Francisco tofirst-generation immigrants fromRomania. His father was asurgeon,^[1] and his grandfather,Constantin Vișoianu, was a formerMinister of Foreign Affairs of Romania.^[4][5] He has a brother.^[1]

Thanks to his childhood experience, he initially wanted to graduate withhistory from theUniversity of California, Berkeley. A third-yearphysiology class taught byRoger Y. Tsien had a great influence on Negulescu, who eventually graduated with adual degree in history and physiology in 1986. He then went on and studiedPhD in physiology under Terry Machen, completing it in 1990.^[1]

Negulescu started his career as apostdoctoral researcher at theUniversity of California, Berkeley and under Michael Cahalan at theUniversity of California, Irvine. He was planning to move to theUniversity of Connecticut whenRoger Y. Tsien asked him to join astartup company he was forming calledAurora 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. WhenVertex Pharmaceuticals acquired Aurora Biosciences in 2001,^[8] he was appointed Senior Vice President of Research.^[1] Negulescu has been leading theSan Diego Research Center of Vertex Pharmaceuticals since 2003.^[9]

Negulescu's research focuses on the therapy ofcystic fibrosis. Cystic fibrosis can be caused by any of the thousands of identifiedmutations in theCFTR protein, anion channel that allowschloride 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] Viahigh-throughput screening, his team atVertex Pharmaceuticals discoveredivacaftor, asmall-moleculepotentiator that increases the probability that mutated CFTR gates will open.^[11][12] Ivacaftor was approved by theFood 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 onin vitro data, due to the small number of patients carrying those rare mutations makingclinical trials impossible.^[14]

Negulescu also led the discovery of another cystic fibrosis drug,lumacaftor, which is known as a "corrector" as it acts as achaperone to help the CFTR protein fold correctly.^[15] Thus, it can be used in patients with Class II mutations, which createmisfolded CFTR protein that cannot reaching thecell 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 oftezacaftor andelexacaftor, 2 other correctors of the CFTR protein.^[21] The triple combinationelexacaftor/tezacaftor/ivacaftor was approved by the FDA in 2019.^[22]

• 2018 -Warren Alpert Foundation Prize^[7]
• 2022 -Shaw Prize in Life Science & Medicine^[23]
• 2023 -Wiley Prize^[24]
• 2024 -Breakthrough Prize in Life Sciences^[25]

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

• Living people
• 21st-century American biologists
• University of California, Berkeley alumni
• American people of Romanian descent

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