Modeling the binding of protoporphyrin IX, verteporfin, and chlorin e6 to SARS-CoV-2 proteins.
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ABSTRACT:
SUBMITTER: Koifman OI
PROVIDER: S-EPMC8118678 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 μmol/L and 0.31 μmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.
| S-EPMC7724564 | biostudies-literature
Project description:Cu (II) protoporphyrin Cu-PP-IX and chlorin Cu-C-e6 were found to have both thin solid film formation and charge carrier transport abilities. In the layers deposited by resistive thermal evaporation, the mobilities of holes and electrons are on the order of 10-5 cm2 V-1 s-1. Organic light-emitting diodes incorporating the dye molecules as emitting dopants demonstrate electroluminescence in the UV and near-IR ranges.
| S-EPMC9964107 | biostudies-literature
Project description:Immunoglobulin G (IgG) is known to bind zinc via the Fc domain. In this study, biotinylated protoporphyrin IX (PPIX) was incubated with human IgG and then zinc-immobilized Sepharose beads (Zn-beads) were added to the mixture. After washing the beads, the binding of biotinylated PPIX with IgG trapped on Zn-beads was detected using alkaline phosphatase (ALP)-labeled avidin. Human IgG and its Fab domain coated on microtiter plate wells recognized biotin-labeled PPIX and its derivatives, Fe-PPIX and Zn-PPIX, whereas the Fc domain showed some extent of reaction only with Zn-PPIX. When rabbit anti-bovine transferrin (Tf) antibodies were incubated with biotinylated PPIX, the binding of anti-Tf antibodies with apo-Tf was indirectly detected using ALP-labeled avidin, suggesting that even if the antibody is modified with PPIX, the antibody-antigen reaction occurs. These results suggest that the IgG Fab domain recognizes PPIX and its derivatives, probably via the recognition of the PPIX ring. It is unlikely that binding between the Fab domain and PPIX affects the Fc domain-zinc interaction or antigen-antibody reaction.
| S-EPMC6640705 | biostudies-literature
Project description:The global situation of diseases transmitted by arthropod-borne viruses such as Dengue (DENV), Yellow Fever (YFV), Chikungunya (CHIKV) and Zika (ZIKV) viruses is alarming and treatment of human infection by these arboviruses faces several challenges. The discovery of broad-spectrum antiviral molecules, able to inactivate different groups of viruses, is an interesting approach. The viral envelope is a common structure among arboviruses, being a potential target for antivirals. Porphyrins are amphipathic molecules able to interact with membranes and absorb light, being widely used in photodynamic therapy. Previously, we showed that heme, Co-protoporphyrin IX (CoPPIX) and Sn-protoporphyrin IX (SnPPIX) directly inactivate DENV and YFV infectious particles. Here we demonstrate that the antiviral activity of these porphyrins can be broadened to CHIKV, ZIKV, Mayaro virus, Sindbis virus and Vesicular Stomatitis virus. Porphyrin treatment causes viral envelope protein loss, affecting viral morphology, adsorption and entry into target cells. Also, light-stimulation enhanced the SnPPIX activity against all tested arboviruses. In summary, CoPPIX and SnPPIX were shown to be efficient broad-spectrum compounds to inactivate medically and veterinary important viruses.
| S-EPMC6023862 | biostudies-literature
Project description:Human serum albumin (HSA) is the main plasma protein responsible for a distribution of drugs in the human circulatory system. The binding to HSA is one of the factors that determines both the pharmacological actions and the side effects of drugs. The derivative of heme, protoporphyrin IX (PpIX), is a hydrophobic photosensitizer widely used in photodynamic diagnosis and therapy of various malignant disorders. Using absorption and fluorescence spectroscopy, it has been demonstrated that PpIX forms complexes with HSA. Its binding sites in the tertiary structure of HSA were found in the subdomains IB and IIA. PpIX binds to HSA in one class of binding sites with the association constant of 1.68 × 10? M-1 and 2.30 × 10? M-1 for an excitation at wavelength ?ex = 280 nm and 295 nm, respectively. The binding interactions between HSA and PpIX have been studied by means of molecular docking simulation using the CLC Drug Discovery Workbench (CLC DDWB) computer program. PpIX creates a strong 'sandwich-type' complex between its highly conjugated porphine system and aromatic side chains of tryptophan and tyrosine. In summary, fluorescent studies on binding interactions between HSA and PpIX have been confirmed by the results of computer simulation.
| S-EPMC6273174 | biostudies-literature
Project description:To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow cytometry and confocal laser scanning microscopy results confirmed Ce6-biotin had higher binding affinity toward biotin-receptor-positive HeLa human cervical carcinoma cells than its precursor, Ce6. Due to the BR-targeting ability of Ce6-biotin, it exhibited stronger cytotoxicity to HeLa cells upon laser irradiation. The IC50 against HeLa cells of Ce6-biotin and Ce6 were 1.28 µM and 2.31 µM, respectively. Furthermore, both Ce6-biotin and Ce6 showed minimal dark toxicity. The selectively enhanced therapeutic efficacy and low dark toxicity suggest that Ce6-biotin is a promising PS for BR-positive-tumor-targeting photodynamic therapy.
| S-EPMC8658943 | biostudies-literature
Project description:BackgroundImproving the water solubility of hydrophobic photosensitizer and increasing its accumulation in tumor tissue are essential for in vivo photodynamic therapy (PDT). Considering commercialization or clinical application in future, it will be promising to achieve these purposes by developing new agents with simple and non-toxic structure.ResultsWe conjugated multiple chlorin e6 (Ce6) molecules to gelatin polymer, synthesizing two types of gelatin-Ce6 conjugates with different amounts of Ce6: gelatin-Ce6-2 and gelatin-Ce6-8. The resulting conjugates remained soluble in aqueous solutions for a longer time than hydrophobic Ce6. The conjugates could generate singlet oxygen and kill tumor cells upon laser irradiation. After intravenous injection into SCC-7 tumor-bearing mice, gelatin-Ce6-2 showed prolonged blood circulation and highly increased accumulation in tumor tissue as observed in real-time imaging in vivo. After laser irradiation, gelatin-Ce6-2 suppressed tumor growth completely and enabled improved PDT compared to free Ce6 and gelatin-Ce6-8.ConclusionsThis work demonstrates that a simple structure based on photosensitizer and gelatin can highly improve water solubility and stability. Superior tumor tissue accumulation and increased therapeutic efficacy of gelatin-Ce6 during in vivo PDT showed its high potential for clinical application.
| S-EPMC6449946 | biostudies-literature
Project description:A recent rational approach to anti-malarial drug design is characterized as "covalent biotherapy" involves linking of two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule. In view of this background and reported anti malaria synergism between artemisinin and quinine; we describe the computer-assisted docking to predict molecular interaction and binding affinity of Artemisinin-Quinine hybrid and its derivatives with the intraparasitic haeme group of human haemoglobin. Starting from a crystallographic structure of Fe-protoporphyrin-IX, binding modes, orientation of peroxide bridge (Fe-O distance), docking score and interaction energy are predicted using the docking molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Seven new ligands were identified with a favourable glide score (XP score) and binding free energy (ΔG) with reference to the experimental structure from a data set of thirty four hybrid derivatives. The result shows the conformational property of the drug-receptor interaction and may lead to rational design and synthesis of improved potent artemisinin based hybrid antimalarial that target haemozoin formation.
| S-EPMC3346024 | biostudies-literature
Project description:The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.
| S-EPMC10648776 | biostudies-literature
Project description:The therapeutic effect of photodynamic therapy (PDT) is highly dependent on the intracellular production of reactive oxygen species (ROS). However, the ROS generated by photosensitizers can be consumed by the highly concentrated glutathione (GSH) in tumor cells, severely impairing the therapeutic effect of PDT. Herein, we synthesized a GSH-scavenging copolymer to deliver photosensitizer chlorin e6 (Ce6). The pyridyl disulfide groups, which have faster reactivity with the thiol groups of GSH than other disulfide groups, were grafted onto a hydrophobic block to encapsulate the Ce6. Under NIR irradiation, the Ce6 generated ROS to kill tumor cells, and the pyridyl disulfide groups depleted the GSH to prevent ROS consumption, which synergistically enhanced the therapeutic effect of PDT. In vitro and in vivo experiments confirmed the combinatory antitumor effect of Ce6-induced ROS generation and the pyridyl disulfide group-induced GSH depletion. Therefore, the pyridyl disulfide group-grafted amphiphilic copolymer provides a more efficient strategy for enhancing PDT and has promising potential for clinical application.
| S-EPMC9346557 | biostudies-literature