Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Harmaline and Human ClpP Activation for Pediatric Diffuse Intrinsic Pontine Glioma (DIPG) Treatment

Morena Miciaccia
ORCID logo ,
Francesca Rizzo
,
Antonella Centonze
ORCID logo ,
Gianfranco Cavallaro
ORCID logo ,
Marialessandra Contino
ORCID logo ,
Domenico Armenise
,
Olga Maria Baldelli
,
Roberta Solidoro
,
Savina Ferorelli
,
Pasquale Scarcia
ORCID logo ,
Gennaro Agrimi
ORCID logo ,
Veronica Zingales
,
Elisa Cimetta
ORCID logo ,
Simone Ronsisvalle
ORCID logo ,
Federica Maria Sipala
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Paola Loguercio Polosa
,
Cosimo Gianluca Fortuna
,
Maria Grazia Perrone
* ORCID logo ,
Antonio Scilimati
ORCID logo
Version 1 : Received: 18 December 2023 / Approved: 22 December 2023 / Online: 22 December 2023 (11:39:39 CET)

A peer-reviewed article of this Preprint also exists.

Miciaccia, M.; Rizzo, F.; Centonze, A.; Cavallaro, G.; Contino, M.; Armenise, D.; Baldelli, O.M.; Solidoro, R.; Ferorelli, S.; Scarcia, P.; Agrimi, G.; Zingales, V.; Cimetta, E.; Ronsisvalle, S.; Sipala, F.M.; Polosa, P.L.; Fortuna, C.G.; Perrone, M.G.; Scilimati, A. Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment. Pharmaceuticals 2024, 17, 135. Miciaccia, M.; Rizzo, F.; Centonze, A.; Cavallaro, G.; Contino, M.; Armenise, D.; Baldelli, O.M.; Solidoro, R.; Ferorelli, S.; Scarcia, P.; Agrimi, G.; Zingales, V.; Cimetta, E.; Ronsisvalle, S.; Sipala, F.M.; Polosa, P.L.; Fortuna, C.G.; Perrone, M.G.; Scilimati, A. Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment. Pharmaceuticals 2024, 17, 135.

Abstract

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 in stabilizing symptoms. In silico and preclinical studies identified ONC201, as a cytotoxic agent against some human cancer cell lines, including DIPG ones. Single crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed to identify hClpP as its main target. 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.

Keywords

Harmaline; hClpP activation; DIPG; Molecular modeling

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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