Mechanisms of Vesicular Stomatitis Virus Inactivation by Protoporphyrin IX, Zinc-Protoporphyrin IX, and Mesoporphyrin IX

Abstract

Virus resistance to antiviral therapies is an increasing concern that makes the development of broad-spectrum antiviral drugs urgent. Targeting of the viral envelope, a component shared by a large number of viruses, emerges as a promising strategy to overcome this problem. Natural and synthetic porphyrins are good candidates for antiviral development due to their relative hydrophobicity and pro-oxidant character. In the present work, we characterized the antiviral activities of protoprophyrin IX (PPIX), Znprotoporphyrin IX (ZnPPIX), and mesoporphyrin IX (MPIX) against vesicular stomatitis virus (VSV) and evaluated the mechanisms involved in this activity. Treatment of VSV with PPIX, ZnPPIX, and MPIX promoted dose-dependent virus inactivation, which was potentiated by porphyrin photoactivation. All three porphyrins inserted into lipid vesicles and disturbed the viral membrane organization. In addition, the porphyrins also affected viral proteins, inducing VSV glycoprotein cross-linking, which was enhanced by porphyrin photoactivation. Virus incubation with sodium azide and ␣-tocopherol partially protected VSV from inactivation by porphyrins, suggesting that singlet oxygen ( 1 O 2 ) was the main reactive oxygen species produced by photoactivation of these molecules. Furthermore, 1 O 2 was detected by 9,10-dimethylanthracene oxidation in photoactivated porphyrin samples, reinforcing this hypothesis. These results reveal the potential therapeutic application of PPIX, ZnPPIX, and MPIX as good models for broad antiviral drug design.KEYWORDS photoactivation, porphyrin, singlet oxygen, vesicular stomatitis virus, viral inactivation D espite the increasing number of antiviral drugs available nowadays, therapeutics for viral diseases often fail due to drug resistance development by the target viruses. In the search for antiviral agents with a broad spectrum of activity against viruses, antiviral agents targeting the viral envelope, a component shared by a large number of viruses, emerge as promising compounds able to overcome the drug resistance problem. Porphyrins, amphipathic molecules able to interact with membranes, appear to be good candidates for the development of such antivirals. Porphyrins are formed by four pyrrole rings linked by methine bonds. The nitrogen atoms in the center of the ring form a pocket able to coordinate metallic ions, conferring to porphyrin the ability to absorb light at additional wavelengths and act in catalytic transformations (1). These activities allow porphyrins to be involved in important biological processes, such as respiration (heme) and photosynthesis (chlorophyll and bacteriochlorophyll) (2).

Photodynamic inactivation of bacteriophage MS2: The A-protein is the target of virus inactivation

“…Photodynamic inactivation (PDI) of viruses has been shown to be an efficient alternative to antiviral agents in the control of resistant and emerging viruses [1][2][3][4][5][6][7][8][9][10]. When irradiated with visible light and in the presence of molecular oxygen in aqueous solution, photosensitisers such as 5,10,15,20-tetrakis (1-methyl-4-pyridinio) porphyrin tetra p-toluenesulfonate (TMPyP) can generate singlet oxygen by a type 2 reaction (and other reactive oxygen species (ROS) by type 1 reaction) [11][12][13].…”

A systematic review of photodynamic therapy as an antiviral treatment: Potential guidance for dealing with SARS-CoV-2

“…In the 26 in vitro articles included in this review as shown in Table 1 , 39 different types of PS were identified, and six articles used more than one PS alternative [ 33 , 37 , 39 , 40 , 42 , 56 ]. In this context, there was a predominance of compounds derived from porphyrin represented 30.7% (n = 12/39), with emphasis on compounds Protoprophyrin IX (PPIX); Zn-protoporphyrin IX (ZnPPIX); Mesoporphyrin IX (MPIX); Porphyrin derivative; Tetraphenylporphyrin (TPP); Neutral 1b and Cationic tripyridylporphyrin-D-galactose 3b; Cationic porphyrin, mono-phenyl-tri-(N-methyl-4-pyridyl)-porphyrin chloride [Tri-P(4)]; Meso-tetraphenylsulfonated porphyrins (TPPMS4); TPPFeS4; TPPMnS4; TPPPdS4; TPPZnS4 and Hematoporphyrin monomethyl ether (HMME) [ 40 , 45 , 48 , 54 , 55 , 56 , 59 ].…”

The Application of Porphyrins and Their Analogues for Inactivation of Viruses

“…The envelope of the vesicular stomatitis virus is a lipid bilayer obtained from the host cell; it contains trimers of one type of integral glycoprotein, called the G-protein, which allows the virus to enter the target cell through endocytosis, and it catalyzes the fusion of viral and endosomal membranes. Dose-dependent inactivation of the virus was enhanced during photoactivation of porphyrins (protoporphyrin IX, Zn (II) protoporphin, mesoporphyrin IX) [ 38 ]. It turned out that all three porphyrins intercalate into lipid vesicles and disrupt the structure of the viral membrane.…”