Genital herpes, most frequently caused by herpes simplex virus 2 (HSV-2) infection, is one of the most prevalent sexually transmitted infections. The current rationale for the treatment of HSV-2 infection involves nucleoside analogs (e.g. acyclovir) to suppress reactivation. Enzymatic oxysterols are endogenous 27-carbon atoms mole-cules produced by enzymatic cholesterol oxidation, and recently emerged as a broad-spectrum host targeting antivirals. In this study, we screened selected members of an in-house synthesized library of oxysterol analogs for their activity against HSV-2, identifying three compounds, named PFM064, PFM067, and PFM069, endowed with 50% effective concentrations (EC50) in the micromolar range, without exerting any apparent cytotoxicity. Moreover, the results obtained showed the ability of the novel derivatives to inhibit both cell-to-cell fusion induced by HSV-2, and the production of an intracellular viral progeny. Further experiments performed with PFM067 (which was selected for more-in-depth studies as the most effective synthetic analog) showed that these molecules act in a late stage of HSV-2 replicative cycle, by sequestering viral glycoproteins in the Golgi compartment, and likely inhibiting the nuclear egress of neo-synthetized viral capsids.Taken together, these results point to PFM067 as a promising chemical scaffold for the development of novel herpetic antivirals.

Identification of oxysterol synthetic analogs as a novel class of late-stage inhibitors of herpes simplex virus 2 replication

Civra, Andrea;Costantino, Matteo;Ronchi, Giulia;Poli, Giuseppe;Lembo, David
2023-01-01

Abstract

Genital herpes, most frequently caused by herpes simplex virus 2 (HSV-2) infection, is one of the most prevalent sexually transmitted infections. The current rationale for the treatment of HSV-2 infection involves nucleoside analogs (e.g. acyclovir) to suppress reactivation. Enzymatic oxysterols are endogenous 27-carbon atoms mole-cules produced by enzymatic cholesterol oxidation, and recently emerged as a broad-spectrum host targeting antivirals. In this study, we screened selected members of an in-house synthesized library of oxysterol analogs for their activity against HSV-2, identifying three compounds, named PFM064, PFM067, and PFM069, endowed with 50% effective concentrations (EC50) in the micromolar range, without exerting any apparent cytotoxicity. Moreover, the results obtained showed the ability of the novel derivatives to inhibit both cell-to-cell fusion induced by HSV-2, and the production of an intracellular viral progeny. Further experiments performed with PFM067 (which was selected for more-in-depth studies as the most effective synthetic analog) showed that these molecules act in a late stage of HSV-2 replicative cycle, by sequestering viral glycoproteins in the Golgi compartment, and likely inhibiting the nuclear egress of neo-synthetized viral capsids.Taken together, these results point to PFM067 as a promising chemical scaffold for the development of novel herpetic antivirals.
2023
Inglese
Esperti anonimi
215
105634
105647
14
Glycoproteins; Herpes simplex virus; Oxysterols; Synthetic derivatives
no
   Progetti PNRR M4C2 Iniziativa 1.3- PE13 INF-ACT: Adesione dell’Università degli Studi di Torino alla Fondazione "INF-ACT - One Health Basic and Translational Research Actions addressing Unmet Needs on Emerging Infectious Disease"
   INF_ACT
   Ministero dell'Università e della Ricerca
   Decreto MUR n. 1554 del 11/10/2022
1 – prodotto con file in versione Open Access (allegherò il file al passo 6 - Carica)
262
7
Civra, Andrea; Costantino, Matteo; Ronchi, Giulia; Pontini, Lorenzo; Poli, Giuseppe; Marinozzi, Maura; Lembo, David
info:eu-repo/semantics/article
open
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1940470
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