Development of novel macrocyclic small molecules that target CTG trinucleotide repeats

被引：10

作者：

Serrano, Julio F. ^{[1
]}

Lee, JuYeon ^{[1
]}

Curet, L. Daniel ^{[1
]}

Hagler, Lauren D. ^{[1
]}

Bonson, Sarah E. ^{[1
]}

Schuster, Emma J. ^{[1
]}

Zimmerman, Steven C. ^{[1
]}

机构：

[1] Univ Illinois, Dept Chem, 600 South Mathews Ave, Urbana, IL 61801 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 13期

基金：

美国国家卫生研究院;

关键词：

Trinucleotide repeats; DNA targeting; Macrocycle; Myotonic dystrophy; Rational design; MYOTONIC-DYSTROPHY; MUSCLEBLIND PROTEINS; DNA; RNA; RECOGNITION; INSTABILITY; ALKYLATION; AUTOMATION; MECHANISMS; DISCOVERY;

D O I：

10.1016/j.bmc.2019.05.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to d(CTG) mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly p-stack in aqueous solutions. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG.CAG)(74).

引用

页码：2978 / 2984

页数：7

共 42 条

[1] A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding [J].

Arambula, Jonathan F. ;

Ramisetty, Sreenivasa Rao ;

Baranger, Anne M. ;

Zimmerman, Steven C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (38) :16068-16073

[2] Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole-imidazole polyamide-chlorambucil conjugates targeting CAG/CTG trinucleotide repeats [J].

Asamitsu, Sefan ;

Kawamoto, Yusuke ;

Hashiya, Fumitaka ;

Hashiya, Kaori ;

Yamamoto, Makoto ;

Kizaki, Seiichiro ;

Bando, Toshikazu ;

Sugiyama, Hiroshi .

BIOORGANIC & MEDICINAL CHEMISTRY, 2014, 22 (17) :4646-4657

[3] The application of DNA and RNA G-quadruplexes to therapeutic medicines [J].

Collie, Gavin W. ;

Parkinson, Gary N. .

CHEMICAL SOCIETY REVIEWS, 2011, 40 (12) :5867-5892

[4] The Emerging Role of RNA as a Therapeutic Target for Small Molecules [J].

Connelly, Colleen M. ;

Moon, Michelle H. ;

Schneekloth, John S., Jr. .

CELL CHEMICAL BIOLOGY, 2016, 23 (09) :1077-1090

[5] Reducing Levels of Toxic RNA with Small Molecules [J].

Coonrod, Leslie A. ;

Nakamori, Masayuki ;

Wang, Wenli ;

Carrell, Samuel ;

Hilton, Cameron L. ;

Bodner, Micah J. ;

Siboni, Ruth B. ;

Docter, Aaron G. ;

Haley, Michael M. ;

Thornton, Charles A. ;

Berglund, J. Andrew .

ACS CHEMICAL BIOLOGY, 2013, 8 (11) :2528-2537

[6] DNA mismatch-specific base flipping by a bisacridine macrocycle [J].

David, A ;

Bleimling, N ;

Beuck, C ;

Lehn, JM ;

Weinhold, E ;

Teulade-Fichou, MP .

CHEMBIOCHEM, 2003, 4 (12) :1326-1331

[7] Molecular recognition of DNA by small molecules [J].

Dervan, PB .

BIOORGANIC & MEDICINAL CHEMISTRY, 2001, 9 (09) :2215-2235

[8] Targeting RNA in mammalian systems with small molecules [J].

Donlic, Anita ;

Hargrove, Amanda E. .

WILEY INTERDISCIPLINARY REVIEWS-RNA, 2018, 9 (04)

[9] Alternative splicing regulation by Muscleblind proteins: from development to disease [J].

Fernandez-Costa, Juan M. ;

Beatriz Llamusi, M. ;

Garcia-Lopez, Amparo ;

Artero, Ruben .

BIOLOGICAL REVIEWS, 2011, 86 (04) :947-958

[10] In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models [J].

Garcia-Lopez, Amparo ;

Llamusi, Beatriz ;

Orzaez, Mar ;

Perez-Paya, Enrique ;

Artero, Ruben D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (29) :11866-11871

← 1 2 3 4 5 →