Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates

M. Mallya; R.L. Phillips; S.A. Saldanha; Bibekbrata Gooptu; S.C. Leigh Brown; D.J. Termine; A.M. Shirvani; Y. Wu; R.N. Sifers; R. Abagyan; D.A. Lomas

doi:10.1021/jm070687z

Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates

M. Mallya, R.L. Phillips, S.A. Saldanha, Bibekbrata Gooptu, S.C. Leigh Brown, D.J. Termine, A.M. Shirvani, Y. Wu, R.N. Sifers, R. Abagyan, D.A. Lomas

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

117 Citations (Scopus)

Abstract

The Z mutant of α-antitrypsin (Glu342Lys) causes a domain swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerization for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z α-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α- antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α-antitrypsin.

Original language	English
Pages (from-to)	5357-5363
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	50
Issue number	22
DOIs	https://doi.org/10.1021/jm070687z
Publication status	Published - 1 Nov 2007

Access to Document

10.1021/jm070687z

Cite this

Mallya, M., Phillips, R. L., Saldanha, S. A., Gooptu, B., Leigh Brown, S. C., Termine, D. J., Shirvani, A. M., Wu, Y., Sifers, R. N., Abagyan, R., & Lomas, D. A. (2007). Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates. Journal of Medicinal Chemistry, 50(22), 5357-5363. https://doi.org/10.1021/jm070687z

@article{d63fb0c86a10484d92ceba03ba89cc45,

title = "Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates",

abstract = "The Z mutant of α-antitrypsin (Glu342Lys) causes a domain swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerization for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z α-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α- antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α-antitrypsin.",

author = "M. Mallya and R.L. Phillips and S.A. Saldanha and Bibekbrata Gooptu and {Leigh Brown}, S.C. and D.J. Termine and A.M. Shirvani and Y. Wu and R.N. Sifers and R. Abagyan and D.A. Lomas",

year = "2007",

month = nov,

day = "1",

doi = "10.1021/jm070687z",

language = "English",

volume = "50",

pages = "5357--5363",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "22",

}

TY - JOUR

T1 - Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates

AU - Mallya, M.

AU - Phillips, R.L.

AU - Saldanha, S.A.

AU - Gooptu, Bibekbrata

AU - Leigh Brown, S.C.

AU - Termine, D.J.

AU - Shirvani, A.M.

AU - Wu, Y.

AU - Sifers, R.N.

AU - Abagyan, R.

AU - Lomas, D.A.

PY - 2007/11/1

Y1 - 2007/11/1

N2 - The Z mutant of α-antitrypsin (Glu342Lys) causes a domain swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerization for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z α-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α- antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α-antitrypsin.

AB - The Z mutant of α-antitrypsin (Glu342Lys) causes a domain swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerization for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z α-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α- antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α-antitrypsin.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-35848929750&md5=506b7e8ed99670fd7fd83e5001d580d1

U2 - 10.1021/jm070687z

DO - 10.1021/jm070687z

M3 - Article

AN - SCOPUS:35848929750

SN - 0022-2623

VL - 50

SP - 5357

EP - 5363

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

Small molecules block the polymerization of Z α- antitrypsin and increase the clearance of intracellular aggregates

Abstract

Access to Document

Other files and links

Fingerprint

Cite this