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A tetracationic porphyrin with dual anti-prion activity.

ABSTRACT: Prions are deadly infectious agents made of PrP^Sc, a misfolded variant of the cellular prion protein (PrP^C) which self-propagates by inducing misfolding of native PrP^C. PrP^Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP^C, eliciting a dual anti-prion effect. Zn(II)-BnPyP binding to a C-terminal pocket destabilizes the native PrP^C fold, hindering conversion to PrP^Sc; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrP^C endocytosis and lysosomal degradation, thus reducing the substrate for PrP^Sc generation. Zn(II)-BnPyP inhibits propagation of different prion strains in vitro, in neuronal cells and organotypic brain cultures. These results identify a PrP^C-targeting compound with an unprecedented dual mechanism of action which might be exploited to achieve anti-prion effects without engendering drug resistance.

SUBMITTER: Masone A

PROVIDER: S-EPMC10448035 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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A tetracationic porphyrin with dual anti-prion activity.

Masone Antonio A Zucchelli Chiara C Caruso Enrico E Lavigna Giada G Eraña Hasier H Giachin Gabriele G Tapella Laura L Comerio Liliana L Restelli Elena E Raimondi Ilaria I Elezgarai Saioa R SR De Leo Federica F Quilici Giacomo G Taiarol Lorenzo L Oldrati Marvin M Lorenzo Nuria L NL García-Martínez Sandra S Cagnotto Alfredo A Lucchetti Jacopo J Gobbi Marco M Vanni Ilaria I Nonno Romolo R Di Bari Michele A MA Tully Mark D MD Cecatiello Valentina V Ciossani Giuseppe G Pasqualato Sebastiano S Van Anken Eelco E Salmona Mario M Castilla Joaquín J Requena Jesús R JR Banfi Stefano S Musco Giovanna G Chiesa Roberto R

iScience 20230727 9

Prions are deadly infectious agents made of PrPSc, a misfolded variant of the cellular prion protein (PrPC) which self-propagates by inducing misfolding of native PrPC. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP ...[more]

PMID: 37636075

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Project description:Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).

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A tetracationic porphyrin with dual anti-prion activity.

Publications

A tetracationic porphyrin with dual anti-prion activity.

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