Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation

Tyler C. Dean; Mu Yang; Mingyong Liu; Jason M. Grayson; Anthony W. DeMartino; Cynthia S. Day; Jingyun Lee; Cristina M. Furdui; Ulrich Bierbach

doi:10.1021/acsmedchemlett.7b00142

Human Serum Albumin-Delivered [Au(PEt₃)]⁺ Is a Potent Inhibitor of T Cell Proliferation

Tyler C. Dean, Mu Yang, Mingyong Liu, Jason M. Grayson, Anthony W. DeMartino, Cynthia S. Day, Jingyun Lee, Cristina M. Furdui, Ulrich Bierbach

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL]ⁿ⁺ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8⁺ T lymphocyte cells. The activity of the compounds correlates with the steric bulk of the phosphine ligands. Thiourea serves as a leaving group that is readily replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective thiourea ligand exchange, the fragments [Au(PEt₃)]⁺ and [Au(JohnPhos)]⁺ (JohnPhos = 1,1′-biphenyl-2-yl)di-tert-butylphosphine) in compounds 1 and 2 were transferred to recombinant human serum albumin (rHSA). PEt₃ promoted efficient modification of Cys34 in HSA (HSA-1), whereas use of bulky JohnPhos as a carrier ligand led to serum protein nonspecifically modified with multiple gold adducts (HSA-2) (Ellman’s test, ESI-TOF MS). HSA-1, but not HSA-2, strongly inhibits T cell proliferation at nanomolar doses. The potential role of HSA as a delivery vehicle in gold-based autoimmune disease treatment is discussed.

Original language	English (US)
Pages (from-to)	572-576
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00142
State	Published - May 11 2017
Externally published	Yes

Bibliographical note

Funding Information:
This work was funded in part by a SPARK grant from Wake Forest Innovation and Commercialization Services, the Arnold and Mabel Beckman Foundation, and by the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (NCI Cancer Center Support Grant P30CA012197). The HRMS spectra were acquired on a Thermo Scientific LTQ Orbitrap instrument, which was purchased with funds provided by the NSF (grant award number 947028).

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

Gold phosphine complexes
human serum albumin
inhibitor screening
T cell proliferation

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1021/acsmedchemlett.7b00142

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title = "Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation",

abstract = "Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL]n+ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8+ T lymphocyte cells. The activity of the compounds correlates with the steric bulk of the phosphine ligands. Thiourea serves as a leaving group that is readily replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective thiourea ligand exchange, the fragments [Au(PEt3)]+ and [Au(JohnPhos)]+ (JohnPhos = 1,1′-biphenyl-2-yl)di-tert-butylphosphine) in compounds 1 and 2 were transferred to recombinant human serum albumin (rHSA). PEt3 promoted efficient modification of Cys34 in HSA (HSA-1), whereas use of bulky JohnPhos as a carrier ligand led to serum protein nonspecifically modified with multiple gold adducts (HSA-2) (Ellman{\textquoteright}s test, ESI-TOF MS). HSA-1, but not HSA-2, strongly inhibits T cell proliferation at nanomolar doses. The potential role of HSA as a delivery vehicle in gold-based autoimmune disease treatment is discussed.",

keywords = "Gold phosphine complexes, human serum albumin, inhibitor screening, T cell proliferation",

author = "Dean, {Tyler C.} and Mu Yang and Mingyong Liu and Grayson, {Jason M.} and DeMartino, {Anthony W.} and Day, {Cynthia S.} and Jingyun Lee and Furdui, {Cristina M.} and Ulrich Bierbach",

note = "Funding Information: This work was funded in part by a SPARK grant from Wake Forest Innovation and Commercialization Services, the Arnold and Mabel Beckman Foundation, and by the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (NCI Cancer Center Support Grant P30CA012197). The HRMS spectra were acquired on a Thermo Scientific LTQ Orbitrap instrument, which was purchased with funds provided by the NSF (grant award number 947028). Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = may,

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doi = "10.1021/acsmedchemlett.7b00142",

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AU - Liu, Mingyong

AU - Grayson, Jason M.

AU - DeMartino, Anthony W.

AU - Day, Cynthia S.

AU - Lee, Jingyun

AU - Furdui, Cristina M.

AU - Bierbach, Ulrich

N1 - Funding Information: This work was funded in part by a SPARK grant from Wake Forest Innovation and Commercialization Services, the Arnold and Mabel Beckman Foundation, and by the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (NCI Cancer Center Support Grant P30CA012197). The HRMS spectra were acquired on a Thermo Scientific LTQ Orbitrap instrument, which was purchased with funds provided by the NSF (grant award number 947028). Publisher Copyright: © 2017 American Chemical Society.

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Y1 - 2017/5/11

N2 - Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL]n+ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8+ T lymphocyte cells. The activity of the compounds correlates with the steric bulk of the phosphine ligands. Thiourea serves as a leaving group that is readily replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective thiourea ligand exchange, the fragments [Au(PEt3)]+ and [Au(JohnPhos)]+ (JohnPhos = 1,1′-biphenyl-2-yl)di-tert-butylphosphine) in compounds 1 and 2 were transferred to recombinant human serum albumin (rHSA). PEt3 promoted efficient modification of Cys34 in HSA (HSA-1), whereas use of bulky JohnPhos as a carrier ligand led to serum protein nonspecifically modified with multiple gold adducts (HSA-2) (Ellman’s test, ESI-TOF MS). HSA-1, but not HSA-2, strongly inhibits T cell proliferation at nanomolar doses. The potential role of HSA as a delivery vehicle in gold-based autoimmune disease treatment is discussed.

AB - Using a modular library format in conjunction with cell viability (MTS) and flow cytometry assays, 90 cationic complexes [AuPL]n+ (P = phosphine ligand; L = thiourea derivative or chloride) were studied for their antiproliferative activity in CD8+ T lymphocyte cells. The activity of the compounds correlates with the steric bulk of the phosphine ligands. Thiourea serves as a leaving group that is readily replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective thiourea ligand exchange, the fragments [Au(PEt3)]+ and [Au(JohnPhos)]+ (JohnPhos = 1,1′-biphenyl-2-yl)di-tert-butylphosphine) in compounds 1 and 2 were transferred to recombinant human serum albumin (rHSA). PEt3 promoted efficient modification of Cys34 in HSA (HSA-1), whereas use of bulky JohnPhos as a carrier ligand led to serum protein nonspecifically modified with multiple gold adducts (HSA-2) (Ellman’s test, ESI-TOF MS). HSA-1, but not HSA-2, strongly inhibits T cell proliferation at nanomolar doses. The potential role of HSA as a delivery vehicle in gold-based autoimmune disease treatment is discussed.

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