2019
DOI: 10.1021/acs.jmedchem.9b00878
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De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX

Abstract: Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron’s ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibito… Show more

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Cited by 36 publications
(31 citation statements)
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“…Peptide boronates were also identified as ClpP inhibitors 80 . From this class, α-aminoboronic acids compounds 8a-c were identified as human ClpP inhibitors with comparable potency with AV167 81 . Virtual modeling of α-aminoboronic acid with human ClpP suggests that the compound interacts with Ser97 and H122 of human ClpP 81 , but physical structures would be necessary to confirm the mechanism of inhibition.…”
Section: Small Molecule Clpp Inhibitors-chemical Probes To Understandmentioning
confidence: 99%
“…Peptide boronates were also identified as ClpP inhibitors 80 . From this class, α-aminoboronic acids compounds 8a-c were identified as human ClpP inhibitors with comparable potency with AV167 81 . Virtual modeling of α-aminoboronic acid with human ClpP suggests that the compound interacts with Ser97 and H122 of human ClpP 81 , but physical structures would be necessary to confirm the mechanism of inhibition.…”
Section: Small Molecule Clpp Inhibitors-chemical Probes To Understandmentioning
confidence: 99%
“…Boron-containing molecules (BCMs) are another class of compounds that targeting both human and bacterial ClpP. Both C-terminal boronic acids 8a−c (α-amino boronic acids) and N-terminal boronic acids WLS6a inhibit ClpXP enzyme activity in cell-free assays [ 170 , 171 ] ( Figure 2 ). Crystal structure of compound-bound SaClpP and virtual modeling of human ClpP suggest the α-amino boronic acids interact with the catalytic serine residue [ 171 ].…”
Section: Therapeutic Development Of Clpxp Ligands As Anti-cancer Agentsmentioning
confidence: 99%
“…Both C-terminal boronic acids 8a−c (α-amino boronic acids) and N-terminal boronic acids WLS6a inhibit ClpXP enzyme activity in cell-free assays [ 170 , 171 ] ( Figure 2 ). Crystal structure of compound-bound SaClpP and virtual modeling of human ClpP suggest the α-amino boronic acids interact with the catalytic serine residue [ 171 ]. Although promising leads for the development of ClpP inhibitors, the stability, potency, and selectivity of these compounds need to be validated and their efficacy in vitro and in vivo needs to be determined.…”
Section: Therapeutic Development Of Clpxp Ligands As Anti-cancer Agentsmentioning
confidence: 99%
“…In the past years, boronic acids have gained importance within numerous research elds, with an unmet versatility as synthetic intermediates and various other applications. 1,2 Peptideboronic acids (PBAs) in particular are used as protease inhibitors [3][4][5] and as covalent ligands in structural biology. 4,6 Bortezomib is the rst FDA-approved PBA and concurrently the rst-inclass proteasome inhibitor.…”
Section: Introductionmentioning
confidence: 99%
“…1). 5,20 However, only derivatives of boro-Phe and boro-Leu have been reported. In 2020, Reyes et al described the asymmetric Rh-catalysed synthesis of a-aminoboronates using a chiral monophosphite ligand.…”
Section: Introductionmentioning
confidence: 99%