Identification of 2-PMPA as a novel inhibitor of cytosolic carboxypeptidases

Lin, Lei; Zheng, Yu; Cao, Peng; Yuchi, Zhiguang; Wu, Hsiao-Ming

doi:10.1016/j.bbrc.2020.10.029

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…Previous studies have shown that missense mutations may disrupt the three-dimensional structure of the CCP1 protein by interfering with protein folding and affecting the shape of the active site, resulting in CCP1 protein dysfunction [ 20 ]. In our analyses of the CCP1 protein expression in the mouse cerebellum, no expression of CCP1 was found in the cerebellum of Nna1 KO mice; however, the cerebellar CCP1 expression of AMS mice after P15 was lower than that of WT mice.…”

Section: Discussionmentioning

confidence: 99%

CCP1, a Regulator of Tubulin Post-Translational Modifications, Potentially Plays an Essential Role in Cerebellar Development

Pang

Araki

Zhou

et al. 2023

IJMS

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The cytosolic carboxypeptidase (CCP) 1 protein, encoded by CCP1, is expressed in cerebellar Purkinje cells (PCs). The dysfunction of CCP1 protein (caused by CCP1 point mutation) and the deletion of CCP1 protein (caused by CCP1 gene knockout) all lead to the degeneration of cerebellar PCs, which leads to cerebellar ataxia. Thus, two CCP1 mutants (i.e., Ataxia and Male Sterility [AMS] mice and Nna1 knockout [KO] mice) are used as disease models. We investigated the cerebellar CCP1 distribution in wild-type (WT), AMS and Nna1 KO mice on postnatal days (P) 7–28 to investigate the differential effects of CCP protein deficiency and disorder on cerebellar development. Immunohistochemical and immunofluorescence studies revealed significant differences in the cerebellar CCP1 expression in WT and mutant mice of P7 and P15, but no significant difference between AMS and Nna1 KO mice. Electron microscopy showed slight abnormality in the nuclear membrane structure of PCs in the AMS and Nna1 KO mice at P15 and significant abnormality with depolymerization and fragmentation of microtubule structure at P21. Using two CCP1 mutant mice strains, we revealed the morphological changes of PCs at postnatal stages and indicated that CCP1 played an important role in cerebellar development, most likely via polyglutamylation.

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Section: Discussionmentioning

confidence: 99%

CCP1, a Regulator of Tubulin Post-Translational Modifications, Potentially Plays an Essential Role in Cerebellar Development

Pang

Araki

Zhou

et al. 2023

IJMS

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“…Beyond PBPs, carboxypeptidases are archetypal enzymes with a carboxylic acid recognition site. Many small molecules containing carboxylic acids are known inhibitors of this class of enzymes, suggesting that these enzymes would be excellent targets for the carboxylate-binding pocket-targeting libraries. − Further, the PDZ domain is another protein interaction module that has a carboxylate-binding site. − PDZ domains are responsible for many cellular functions such as signal transduction and metabolism and are included in many different types of proteins. Small molecules that block PDZ domain interactions could potentially treat multiple disease states including viral infections or cancers. , A wide range of PDZ domain inhibitors have been discovered, and many of these contain carboxylic acid, suggesting that these, too, are appropriate targets for our focused library. − It will be of great interest to apply the carboxylate-binding pocket-targeting library to screen against various other clinically relevant targets.…”

Section: Discussionmentioning

confidence: 99%

Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

Park,

Fan,

Chamakuri

et al. 2023

J. Med. Chem.

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β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the βlactamase enzyme−substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 10 6 compounds, each containing a carboxylic acid or a tetrazole as an enzyme recognition element, was designed, constructed, and used to identify OXA-48 and NDM-1 inhibitors with micromolar to nanomolar potency. Further optimization led to NDM-1 inhibitors with increased potencies and biological activities. This work demonstrates that the carboxylate-binding pocket-targeting DECL, designed based on substrate binding information, aids in inhibitor identification and led to the discovery of novel non-β-lactam pharmacophores for the development of β-lactamase inhibitors for enzymes of different structural and mechanistic classes.

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“…In fact, a recent study showed the therapeutic potential of 2-PMPA in the treatment of glioblastoma ( Gao et al, 2021 ). New opportunities may also arise using 2-PMPA as a nephron-protective strategy in PSMA-targeted prostate cancer radiotherapy ( Kratochwil et al, 2015 ; Chatalic et al, 2016 ) or use of 2-PMPA as an inhibitor of cytosolic carboxypeptidases ( Wang et al, 2020 ). Despite its proven utility in multiple preclinical models, clinical use of 2-PMPA remains problematic due to its poor pharmacokinetic profile including low cellular uptake, low oral bioavailability, and minimal brain penetration caused by its strongly polar character.…”

Section: 2-(phosphonomethyl) Pentanedioic Acid 2-pmpamentioning

confidence: 99%

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

et al. 2022

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Compounds with a phosphonate group, i.e., –P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called “open-ring” derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44–80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

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Identification of 2-PMPA as a novel inhibitor of cytosolic carboxypeptidases

Cited by 5 publications

References 25 publications

CCP1, a Regulator of Tubulin Post-Translational Modifications, Potentially Plays an Essential Role in Cerebellar Development

CCP1, a Regulator of Tubulin Post-Translational Modifications, Potentially Plays an Essential Role in Cerebellar Development

Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

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