Photodynamic Inhibition of Herpes Simplex Virus 1 Infection by Tricationic Amphiphilic Porphyrin with a Long Alkyl Chain

Abstract

Photodynamic therapy (PDT) is broadly used to treat different tumors, and it is a rapidly developing approach to inactivating or inhibiting the replication of fungi, bacteria, and viruses. Herpes simplex virus 1 (HSV-1) is an important human pathogen and a frequently used model to study the effects of PDT on enveloped viruses. Although many photosensitizers (PSs) have been tested for their antiviral properties, analyses are usually limited to assessing the reduction in viral yield, and thus the molecular mechanisms of photodynamic inactivation (PDI) remain poorly understood. In this study, we investigated the antiviral properties of TMPyP3-C17H35, a tricationic amphiphilic porphyrin-based PS with a long alkyl chain. We show that light-activated TMPyP3-C17H35 can efficiently block virus replication at certain nM concentrations without exerting obvious cytotoxicity. Moreover, we show that the levels of viral proteins (immediate-early, early, and late genes) were greatly reduced in cells treated with subtoxic concentrations of TMPyP3-C17H35, resulting in markedly decreased viral replication. Interestingly, we observed a strong inhibitory effect of TMPyP3-C17H35 on the virus yield only when cells were treated before or shortly after infection. In addition to the antiviral activity of the internalized compound, we show that the compound dramatically reduces the infectivity of free virus in the supernatant. Overall, our results demonstrate that activated TMPyP3-C17H35 effectively inhibits HSV-1 replication and that it can be further developed as a potential novel treatment and used as a model to study photodynamic antimicrobial chemotherapy.

Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action

“…virals (Section 3.2), but it was later shown that the compounds act as membrane-targeted photosensitizers [491][492][493]. Cationic imidazolyl and pyridyl porphyrins were characterized as promising photosensitizing antivirals against SARS-CoV-2 and HSV-1 [494,495]. A natural chlorine photosensitizer, pheophorbide a, inactivates HSV-1, HSV-2, MERS-CoV, SARS-CoV-2, YFV, HCV, and SINV, by targeting the lipid envelope [496,497] (Table 7).…”

“…HSV-1 0.006 [469] gymnochrome B dengue 0.029 [475] hypocrellin A HSV-1 0.015 [469] hypocrellin B HSV-1 0.025 [469] 5-(perylen- virals (Section 3.2), but it was later shown that the compounds act as membrane-targeted photosensitizers [491][492][493]. Cationic imidazolyl and pyridyl porphyrins were characterized as promising photosensitizing antivirals against SARS-CoV-2 and HSV-1 [494,495]. A natural chlorine photosensitizer, pheophorbide a, inactivates HSV-1, HSV-2, MERS-CoV, SARS-CoV-2, YFV, HCV, and SINV, by targeting the lipid envelope [496,497] (Table 7).…”

Systemic Effects of Photoactivated 5,10,15,20-tetrakis(N-methylpyridinium-3-yl) Porphyrin on Healthy Drosophila melanogaster

“…Cationic 5,10,15,20-tetrakis( N -methylpyridinium-3-yl)-porphyrin (TMPyP3) is a positional isomer of TMPyP4 with similar chemical properties ( Figure 1 ). The addition of a long alkyl chain to tripyridylporphyrin resulted in antiviral effects and provided a model for photodynamic antimicrobial chemotherapy [ 13 ], while N -methylated and N -oxidized tripyridylporphyrins with long alkyl chains have shown strong PDT effects and inhibitory activity in sphingolipid metabolism, suggesting a potential for the treatment of cancerous cells [ 14 ]. While these results are encouraging, it is important to note that they were obtained in cell cultures, leaving the specificity in and effectiveness on tumors in an in vivo model unknown.…”