• Je něco špatně v tomto záznamu ?

Extensive targeting of chemical space at the prime side of ketoamide inhibitors of rhomboid proteases by branched substituents empowers their selectivity and potency

K. Bach, J. Dohnálek, J. Škerlová, J. Kuzmík, E. Poláchová, S. Stanchev, P. Majer, J. Fanfrlík, A. Pecina, J. Řezáč, M. Lepšík, V. Borshchevskiy, V. Polovinkin, K. Strisovsky

. 2024 ; 275 (-) : 116606. [pub] 20240617

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018986

Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24018986
003      
CZ-PrNML
005      
20241024111209.0
007      
ta
008      
241015e20240617fr f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.ejmech.2024.116606 $2 doi
035    __
$a (PubMed)38901105
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a fr
100    1_
$a Bach, Kathrin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; Department of Molecular Genetics, Faculty of Science, Charles University, Viničná 5, Prague, 128 44, Czech Republic
245    10
$a Extensive targeting of chemical space at the prime side of ketoamide inhibitors of rhomboid proteases by branched substituents empowers their selectivity and potency / $c K. Bach, J. Dohnálek, J. Škerlová, J. Kuzmík, E. Poláchová, S. Stanchev, P. Majer, J. Fanfrlík, A. Pecina, J. Řezáč, M. Lepšík, V. Borshchevskiy, V. Polovinkin, K. Strisovsky
520    9_
$a Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.
650    _2
$a lidé $7 D006801
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
650    _2
$a molekulární struktura $7 D015394
650    12
$a amidy $x chemie $x farmakologie $x chemická syntéza $7 D000577
650    _2
$a krystalografie rentgenová $7 D018360
650    _2
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a inhibitory proteas $x farmakologie $x chemie $x chemická syntéza $x metabolismus $7 D011480
650    _2
$a molekulární modely $7 D008958
655    _2
$a časopisecké články $7 D016428
700    1_
$a Dohnálek, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; University of Chemistry and Technology, Technická 5, Prague, 166 28, Czech Republic
700    1_
$a Škerlová, Jana $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Kuzmík, Ján $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Poláchová, Edita $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 32, Prague, 121 08, Czech Republic
700    1_
$a Stanchev, Stancho $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Fanfrlík, Jindřich $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Pecina, Adam $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Řezáč, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Lepšík, Martin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic
700    1_
$a Borshchevskiy, Valentin $u Institute of Biological Information Processing 7, IBI-7 (Structural Biochemistry) Forschungszentrum Jülich 52428 Jülich, Germany
700    1_
$a Polovinkin, Vitaly $u ELI Beamlines Centre, ELI ERIC, Za Radnicí 835, 252 41, Dolní Břežany, Czech Republic
700    1_
$a Strisovsky, Kvido $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic. Electronic address: kvido.strisovsky@uochb.cas.cz
773    0_
$w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 275 (20240617), s. 116606
856    41
$u https://pubmed.ncbi.nlm.nih.gov/38901105 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20241015 $b ABA008
991    __
$a 20241024111202 $b ABA008
999    __
$a ok $b bmc $g 2201677 $s 1230959
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 275 $c - $d 116606 $e 20240617 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628
LZP    __
$a Pubmed-20241015

Najít záznam

Citační ukazatele

Možnosti archivace