Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Oct 4;3(12):1024-8.
doi: 10.1021/ml300241m. eCollection 2012 Dec 13.

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

John Wityak  1 , Michael E Prime  2 , Frederick A Brookfield  2 , Stephen M Courtney  2 , Sayeh Erfan  2 , Siw Johnsen  2 , Peter D Johnson  2 , Marie Li  2 , Richard W Marston  2 , Laura Reed  2 , Darshan Vaidya  2 , Sabine Schaertl  3 , Anna Pedret-Dunn  2 , Maria Beconi  1 , Douglas Macdonald  1 , Ignacio Muñoz-Sanjuan  1 , Celia Dominguez  1
Affiliations

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

John Wityak et al. ACS Med Chem Lett. .

Abstract

We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.

Keywords: acrylamides; celiac disease; in vitro ADME; plasma stability; polar surface area.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Lysine-based irreversible inhibitors of TG2 from Marrano et al.
Figure 2
Figure 2
Lysine scaffold replacements 5–7.
See this image and copyright information in PMC

References

    1. Greenberg C. S.; Birckbichler R. H. Transglutaminases: Multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 1991, 5, 3071–3077. - PubMed
    1. Im M.-J.; Riek P.; Graham R. A novel guanine nucleotide-binding protein coupled to the α1-adrenergic receptor. J. Biol. Chem. 1990, 265, 18952–18960. - PubMed
    1. Lai T.-S.; Slaughter T.; Peoples K.; Hettasch J.; Greenburg C. Regulation of human tissue transglutaminase function by magnesium-nucleotide complexes. J. Biol. Chem. 1998, 273, 1776–1781. - PubMed
    1. Hasegawa G.; Suwa M.; Ichikawa Y.; Ohtsuka T.; Kumagai S.; Kikuchi M.; Sato Y.; Saito Y. A novel function of tissue-type transglutaminase: protein disulfide isomerase. Biochem. J. 2003, 373, 793–803. - PMC - PubMed
    1. Pinkas D.; Strop P.; Brunger A.; Khosla C. Transglutaminase 2 undergoes a large conformational change upon activation. PLOS Biol. 2007, 5, 2788–2796. - PMC - PubMed

LinkOut - more resources