• Something wrong with this record ?

Enzymatic Preparation of 2'-5',3'-5'-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

B. Novotná, L. Vaneková, M. Zavřel, M. Buděšínský, M. Dejmek, M. Smola, O. Gutten, ZA. Tehrani, M. Pimková Polidarová, A. Brázdová, R. Liboska, I. Štěpánek, Z. Vavřina, T. Jandušík, R. Nencka, L. Rulíšek, E. Bouřa, J. Brynda, O. Páv, G. Birkuš,

. 2019 ; 62 (23) : 10676-10690. [pub] 20191127

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20023337

Cyclic dinucleotides are second messengers in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB (IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling cascades. In this work, we describe an enzymatic preparation of 2'-5',3'-5'-cyclic dinucleotides (2'3'CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse, and chicken. We profile substrate specificity of these enzymes by employing a small library of nucleotide-5'-triphosphate (NTP) analogues and use them to prepare 33 2'3'CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokine and chemokine induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure-activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20023337
003      
CZ-PrNML
005      
20230519085530.0
007      
ta
008      
201125s2019 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acs.jmedchem.9b01062 $2 doi
035    __
$a (PubMed)31715099
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Novotná, Barbora $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. Faculty of Science , Charles University , Prague 110 00 , Czech Republic.
245    10
$a Enzymatic Preparation of 2'-5',3'-5'-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations / $c B. Novotná, L. Vaneková, M. Zavřel, M. Buděšínský, M. Dejmek, M. Smola, O. Gutten, ZA. Tehrani, M. Pimková Polidarová, A. Brázdová, R. Liboska, I. Štěpánek, Z. Vavřina, T. Jandušík, R. Nencka, L. Rulíšek, E. Bouřa, J. Brynda, O. Páv, G. Birkuš,
520    9_
$a Cyclic dinucleotides are second messengers in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB (IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling cascades. In this work, we describe an enzymatic preparation of 2'-5',3'-5'-cyclic dinucleotides (2'3'CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse, and chicken. We profile substrate specificity of these enzymes by employing a small library of nucleotide-5'-triphosphate (NTP) analogues and use them to prepare 33 2'3'CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokine and chemokine induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure-activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.
650    _2
$a biotest $7 D001681
650    _2
$a počítačová simulace $7 D003198
650    _2
$a cytokiny $x metabolismus $7 D016207
650    _2
$a regulace genové exprese $x účinky léků $7 D005786
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a leukocyty mononukleární $x účinky léků $7 D007963
650    _2
$a membránové proteiny $x chemie $x metabolismus $7 D008565
650    _2
$a nukleotidy cyklické $x chemická syntéza $x farmakologie $7 D009712
650    _2
$a konformace proteinů $7 D011487
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Vaneková, Lenka $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. Faculty of Science , Charles University , Prague 110 00 , Czech Republic.
700    1_
$a Zavřel, Martin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Buděšínský, Miloš $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Dejmek, Milan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Smola, Miroslav $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Gutten, Ondrej $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Tehrani, Zahra Aliakbar $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Pimková Polidarová, Markéta $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. Faculty of Science , Charles University , Prague 110 00 , Czech Republic.
700    1_
$a Brázdová, Andrea $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. $7 ntk2015859863
700    1_
$a Liboska, Radek $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Štěpánek, Ivan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Vavřina, Zdeněk $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. Faculty of Science , Charles University , Prague 110 00 , Czech Republic.
700    1_
$a Jandušík, Tomáš $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. Faculty of Food and Biochemical Technology , University of Chemistry and Technology , Prague 166 28 , Czech Republic.
700    1_
$a Nencka, Radim $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Rulíšek, Lubomír $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Bouřa, Evžen $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Brynda, Jiří $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Páv, Ondřej $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic.
700    1_
$a Birkuš, Gabriel, $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and Gilead Sciences Research Centre at IOCB , Flemingovo nam. 2 , Prague 16610 , Czech Republic. $d 1972- $7 xx0301324
773    0_
$w MED00010049 $t Journal of medicinal chemistry $x 1520-4804 $g Roč. 62, č. 23 (2019), s. 10676-10690
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31715099 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20201125 $b ABA008
991    __
$a 20230519085523 $b ABA008
999    __
$a ok $b bmc $g 1595656 $s 1114013
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 62 $c 23 $d 10676-10690 $e 20191127 $i 1520-4804 $m Journal of medicinal chemistry $n J Med Chem $x MED00010049
LZP    __
$a Pubmed-20201125

Find record

Citation metrics

Archiving options