• Je něco špatně v tomto záznamu ?

On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents

R. Kryštůfek, V. Verner, P. Šácha, M. Hadzima, F. Trajhan, J. Starková, E. Tloušt'ová, A. Dvořáková, A. Pecina, J. Brynda, K. Chalupský, M. Hájek, MJ. Boucher, P. Majer, J. Řezáč, HD. Madhani, CS. Craik, J. Konvalinka

. 2025 ; 68 (9) : 9623-9637. [pub] 20250422

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25015775

Grantová podpora
F32 AI152270 NIAID NIH HHS - United States
U54 AI170792 NIAID NIH HHS - United States

Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25015775
003      
CZ-PrNML
005      
20250731091224.0
007      
ta
008      
250708s2025 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acs.jmedchem.5c00396 $2 doi
035    __
$a (PubMed)40262033
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Kryštůfek, Robin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic $1 https://orcid.org/0000000340961159
245    10
$a On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents / $c R. Kryštůfek, V. Verner, P. Šácha, M. Hadzima, F. Trajhan, J. Starková, E. Tloušt'ová, A. Dvořáková, A. Pecina, J. Brynda, K. Chalupský, M. Hájek, MJ. Boucher, P. Majer, J. Řezáč, HD. Madhani, CS. Craik, J. Konvalinka
520    9_
$a Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.
650    12
$a Cryptococcus neoformans $x účinky léků $x enzymologie $7 D003455
650    12
$a antifungální látky $x farmakologie $x chemie $x chemická syntéza $x farmakokinetika $7 D000935
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
650    12
$a makrocyklické sloučeniny $x farmakologie $x chemie $x chemická syntéza $x farmakokinetika $7 D047028
650    _2
$a mikrobiální testy citlivosti $7 D008826
650    _2
$a zvířata $7 D000818
650    _2
$a lidé $7 D006801
650    12
$a inhibitory proteas $x farmakologie $x chemie $x chemická syntéza $x farmakokinetika $7 D011480
655    _2
$a časopisecké články $7 D016428
700    1_
$a Verner, Václav $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $1 https://orcid.org/0009000341904698
700    1_
$a Šácha, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic
700    1_
$a Hadzima, Martin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Trajhan, Filip $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic $1 https://orcid.org/0009000065065292
700    1_
$a Starková, Jana $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Tloušt'ová, Eva $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Dvořáková, Alexandra $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Pecina, Adam $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $1 https://orcid.org/0000000338907831
700    1_
$a Brynda, Jiří $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, Prague 4 14220, Czech Republic
700    1_
$a Chalupský, Karel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Hájek, Miroslav $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Boucher, Michael J $u Department of Biochemistry & Biophysics, University of California San Francisco, UCSF Genentech Hall, 600 16th St Rm N374, San Francisco, California 94158, United States
700    1_
$a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Řezáč, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic
700    1_
$a Madhani, Hiten D $u Department of Biochemistry & Biophysics, University of California San Francisco, UCSF Genentech Hall, 600 16th St Rm N374, San Francisco, California 94158, United States
700    1_
$a Craik, Charles S $u Department of Pharmaceutical Chemistry, University of California San Francisco, UCSF Genentech Hall, 600 16th St Rm S512, San Francisco, California 94158, United States $1 https://orcid.org/0000000177049185
700    1_
$a Konvalinka, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic $1 https://orcid.org/0000000306959266 $7 mzk2004208597
773    0_
$w MED00010049 $t Journal of medicinal chemistry $x 1520-4804 $g Roč. 68, č. 9 (2025), s. 9623-9637
856    41
$u https://pubmed.ncbi.nlm.nih.gov/40262033 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250708 $b ABA008
991    __
$a 20250731091219 $b ABA008
999    __
$a ok $b bmc $g 2366546 $s 1252900
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2025 $b 68 $c 9 $d 9623-9637 $e 20250422 $i 1520-4804 $m Journal of medicinal chemistry $n J Med Chem $x MED00010049
GRA    __
$a F32 AI152270 $p NIAID NIH HHS $2 United States
GRA    __
$a U54 AI170792 $p NIAID NIH HHS $2 United States
LZP    __
$a Pubmed-20250708

Najít záznam

Citační ukazatele

Možnosti archivace