Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment
Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of β-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
|---|---|
| Enthalten in: |
Pharmaceuticals (Basel, Switzerland) - 17(2024), 1 vom: 19. Jan. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Miciaccia, Morena [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
DIPG |
|---|
| Anmerkungen: |
Date Revised 29.01.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/ph17010135 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367664232 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367664232 | ||
| 003 | DE-627 | ||
| 005 | 20240129232207.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240126s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ph17010135 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1274.xml |
| 035 | |a (DE-627)NLM367664232 | ||
| 035 | |a (NLM)38276008 | ||
| 035 | |a (PII)135 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Miciaccia, Morena |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 29.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of β-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DIPG | |
| 650 | 4 | |a hClpP activation | |
| 650 | 4 | |a harmaline | |
| 650 | 4 | |a molecular modeling | |
| 700 | 1 | |a Rizzo, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Centonze, Antonella |e verfasserin |4 aut | |
| 700 | 1 | |a Cavallaro, Gianfranco |e verfasserin |4 aut | |
| 700 | 1 | |a Contino, Marialessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Armenise, Domenico |e verfasserin |4 aut | |
| 700 | 1 | |a Baldelli, Olga Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Solidoro, Roberta |e verfasserin |4 aut | |
| 700 | 1 | |a Ferorelli, Savina |e verfasserin |4 aut | |
| 700 | 1 | |a Scarcia, Pasquale |e verfasserin |4 aut | |
| 700 | 1 | |a Agrimi, Gennaro |e verfasserin |4 aut | |
| 700 | 1 | |a Zingales, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Cimetta, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Ronsisvalle, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Sipala, Federica Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Polosa, Paola Loguercio |e verfasserin |4 aut | |
| 700 | 1 | |a Fortuna, Cosimo Gianluca |e verfasserin |4 aut | |
| 700 | 1 | |a Perrone, Maria Grazia |e verfasserin |4 aut | |
| 700 | 1 | |a Scilimati, Antonio |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pharmaceuticals (Basel, Switzerland) |d 2009 |g 17(2024), 1 vom: 19. Jan. |w (DE-627)NLM199619514 |x 1424-8247 |7 nnns |
| 773 | 1 | 8 | |g volume:17 |g year:2024 |g number:1 |g day:19 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ph17010135 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 17 |j 2024 |e 1 |b 19 |c 01 | ||