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9 pages, 1272 KiB

Open AccessArticle

Kaempferol Interferes with Varicella-Zoster Virus Replication in Human Foreskin Fibroblasts

by Subin Park, Na-Eun Kim, Bang Ju Park, Hak Cheol Kwon and Yoon-Jae Song

Pharmaceuticals 2022, 15(12), 1582; https://doi.org/10.3390/ph15121582 - 19 Dec 2022

Cited by 10 | Viewed by 1977

Abstract

Kaempferol, a natural flavonoid abundantly found in plants, is known to have pharmacological properties, such as anti-inflammatory and anti-cancer effects. In this study, we investigated the antiviral effects of kaempferol against a varicella-zoster virus (VZV) clinical isolate in vitro. We found that kaempferol [...] Read more.

Kaempferol, a natural flavonoid abundantly found in plants, is known to have pharmacological properties, such as anti-inflammatory and anti-cancer effects. In this study, we investigated the antiviral effects of kaempferol against a varicella-zoster virus (VZV) clinical isolate in vitro. We found that kaempferol significantly inhibited VZV replication without exhibiting cytotoxicity. Kaempferol exerted its antiviral effect at a similar stage of the VZV life cycle as acyclovir, which inhibits VZV DNA replication. Taken together, our results suggest that kaempferol inhibits VZV infection by blocking the DNA replication stage in the viral life cycle. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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16 pages, 2625 KiB

Open AccessArticle

In Vitro Anti-Influenza Virus Activity of Non-Polar Primula veris subsp. veris Extract

by Aristides G. Eliopoulos, Apostolis Angelis, Anastasia Liakakou and Leandros A. Skaltsounis

Pharmaceuticals 2022, 15(12), 1513; https://doi.org/10.3390/ph15121513 - 5 Dec 2022

Cited by 3 | Viewed by 2298

Abstract

Medicinal plants have long been recognized as a tremendous source of candidate compounds for the development of pharmaceuticals, including anti-viral agents. Herein, we report the identification of anti-influenza virus activity in non-polar Primula veris L. subsp. veris extracts. We show that P. veris [...] Read more.

Medicinal plants have long been recognized as a tremendous source of candidate compounds for the development of pharmaceuticals, including anti-viral agents. Herein, we report the identification of anti-influenza virus activity in non-polar Primula veris L. subsp. veris extracts. We show that P. veris subsp. veris flower extracts, obtained using supercritical fluid or ultrasound-based extraction, possess virucidal/virus inactivation properties and confer prophylactic and therapeutic effects against influenza virus-induced cytolysis in vitro. By GC-MS and UPLC-HRMS analysis of non-polar P. veris subsp. veris extracts we identified terpenes, flavones, tocopherols, and other classes of phytochemicals with known or putative anti-influenza properties. In silico prediction of cellular functions and molecular pathways affected by these phytochemicals suggests putative effects on signal transduction, inflammasome, and cell death pathways that are relevant to influenza virus pathogenesis. Combining P. veris subsp. veris with extracts of medicinal plants with proven anti-influenza activity such as Echinacea purpurea (L.) Moench and Cistus creticus L. subsp. creticus achieves an impressive protective effect against infection by influenza virus H1N1 in vitro and reduced progeny virus production by infected cells. Collectively, these findings uncover a previously uncharted biological property of non-polar P. veris flower extracts that warrants further studies to assess clinical efficacy. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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15 pages, 2202 KiB

Open AccessArticle

Antiviral Effect of Stenocline ericoides DC. and Stenocline inuloides DC., Two Flavonoid-Rich Endemic Plants from Madagascar, against Dengue and Zika Viruses

by Fenia D. Ramiharimanana, Juliano G. Haddad, Maminiaina A. Andrianavalonirina, Cécile Apel, Florent Olivon, Nicolas Diotel, Philippe Desprès, Voahangy Vestalys Ramanandraibe and Chaker El Kalamouni

Pharmaceuticals 2022, 15(12), 1500; https://doi.org/10.3390/ph15121500 - 30 Nov 2022

Cited by 2 | Viewed by 2200

Abstract

Dengue and Zika viruses are identified as the most medically important arthropod-borne viral pathogens. Over the past 20 years, the global dengue incidence has dramatically increased with epidemics of severe dengue where the case fatality rate can reach up to 20% in untreated [...] Read more.

Dengue and Zika viruses are identified as the most medically important arthropod-borne viral pathogens. Over the past 20 years, the global dengue incidence has dramatically increased with epidemics of severe dengue where the case fatality rate can reach up to 20% in untreated patients. The association between Zika virus infection and severe congenital anomalies was first reported in 2015. Today no specific antiviral therapies are available for dengue and Zika virus infections, accentuating the need of adapted antiviral strategies based on medicinal plant drug discovery. Plants are a potential source of antiviral phytocompounds which act primarily by blocking virus entry in the host-cell. In the present study, we evaluated whether crude extracts from Stenocline ericoides DC. and Stenocline inuloides DC., two endemic plants from Madagascar, may have antiviral effects against dengue and Zika viruses. We showed that S. ericoides has virucidal action whereas S. inuloides inhibits the early steps of virus infection with a non-cytotoxic effect in human cells. The administration of S. ericoides and S. inuloides extracts in zebrafish had no effect on the behavior of animals at the active doses against dengue and Zika viruses, suggesting the absence of adverse effects at these doses. LC-HRMS² and molecular networking analyses revealed the richness of these two plants in polyphenols and flavonoid with the presence of clusters of phytocompounds specific to each Stenocline species. Consequently, S. ericoides and S. inuloides represent potential sources for natural and safe antiviral phytocompounds against flaviviruses of medical concern. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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14 pages, 6489 KiB

Open AccessArticle

Effect of Structural Differences in Naringenin, Prenylated Naringenin, and Their Derivatives on the Anti-Influenza Virus Activity and Cellular Uptake of Their Flavanones

by Ryosuke Morimoto, Chiaki Matsubara, Akari Hanada, Yuta Omoe, Tokutaro Ogata and Yuji Isegawa

Pharmaceuticals 2022, 15(12), 1480; https://doi.org/10.3390/ph15121480 - 28 Nov 2022

Cited by 10 | Viewed by 2050

Abstract

Vaccines and antiviral drugs are widely used to treat influenza infection. However, they cannot rapidly respond to drug-resistant viruses. Therefore, new anti-influenza virus strategies are required. Naringenin is a flavonoid with potential for new antiviral strategies. In this study, we evaluated the antiviral [...] Read more.

Vaccines and antiviral drugs are widely used to treat influenza infection. However, they cannot rapidly respond to drug-resistant viruses. Therefore, new anti-influenza virus strategies are required. Naringenin is a flavonoid with potential for new antiviral strategies. In this study, we evaluated the antiviral effects of naringenin derivatives and examined the relationship between their cellular uptake and antiviral effects. Madin–Darby canine kidney (MDCK) cells were infected with the A/PR/8/34 strain and exposed to the compound-containing medium for 24 h. The amount of virus in the supernatant was calculated using focus-forming reduction assay. Antiviral activity was evaluated using IC₅₀ and CC₅₀ values. Cells were exposed to a constant concentration of naringenin or prenylated naringenin, and intracellular uptake and distribution were evaluated using a fluorescence microscope. Prenylated naringenin showed strong anti-influenza virus effects, and the amount of intracellular uptake was revealed by the strong intracellular fluorescence. In addition, intracellular distribution differed depending on the position of the prenyl group. The steric factor of naringenin is deeply involved in influenza A virus activity, and prenyl groups are desirable. Furthermore, the prenyl group affects cellular affinity, and the uptake mechanism differs depending on its position. These results provide important information on antiviral strategies. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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15 pages, 2005 KiB

Open AccessArticle

Novel Aporphine- and Proaporphine–Clerodane Hybrids Identified from the Barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula with Strong Anti-DENV2 Activity

by I-Wen Lo, Geng-You Liao, Jin-Ching Lee, Chi-I Chang, Yang-Chang Wu, Yen-Yu Chen, Shang-Pin Liu, Huey-Jen Su, Chih-I Liu, Chia-Yi Kuo, Zheng-Yu Lin, Tsung-Lin Li, Yun-Sheng Lin and Chia-Ching Liaw

Pharmaceuticals 2022, 15(10), 1218; https://doi.org/10.3390/ph15101218 - 30 Sep 2022

Cited by 4 | Viewed by 2175

Abstract

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two [...] Read more.

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C–C or N–C covalent linkage. Here, we report four structurally attractive diterpene–alkaloid conjugates polyalongarins A–D (1–4), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese Polyalthia longifolia (Sonn.) Thwaites var. pendula. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of 1. Compounds 1–4 were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC₅₀ (2.8–6.4 μM) and CC₅₀ values (50.4–200 μM). The inhibitory mechanism of 1–4 on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of 1–4 and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane–aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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17 pages, 6694 KiB

Open AccessEditor’s ChoiceArticle

Protocetraric and Salazinic Acids as Potential Inhibitors of SARS-CoV-2 3CL Protease: Biochemical, Cytotoxic, and Computational Characterization of Depsidones as Slow-Binding Inactivators

by Lorenza Fagnani, Lisaurora Nazzicone, Pierangelo Bellio, Nicola Franceschini, Donatella Tondi, Andrea Verri, Sabrina Petricca, Roberto Iorio, Gianfranco Amicosante, Mariagrazia Perilli and Giuseppe Celenza

Pharmaceuticals 2022, 15(6), 714; https://doi.org/10.3390/ph15060714 - 4 Jun 2022

Cited by 3 | Viewed by 2634

Abstract

The study investigated the inhibitory activity of protocetraric and salazinic acids against SARS-CoV-2 3CL^pro. The kinetic parameters were determined by microtiter plate-reading fluorimeter using a fluorogenic substrate. The cytotoxic activity was tested on murine Sertoli TM4 cells. In silico analysis was [...] Read more.

The study investigated the inhibitory activity of protocetraric and salazinic acids against SARS-CoV-2 3CL^pro. The kinetic parameters were determined by microtiter plate-reading fluorimeter using a fluorogenic substrate. The cytotoxic activity was tested on murine Sertoli TM4 cells. In silico analysis was performed to ascertain the nature of the binding with the 3CL^pro. The compounds are slow-binding inactivators of 3CL^pro with a K_i of 3.95 μM and 3.77 μM for protocetraric and salazinic acid, respectively, and inhibitory efficiency k_inact/K_i at about 3 × 10⁻⁵ s⁻¹µM⁻¹. The mechanism of inhibition shows that both compounds act as competitive inhibitors with the formation of a stable covalent adduct. The viability assay on epithelial cells revealed that none of them shows cytotoxicity up to 80 μM, which is well below the K_i values. By molecular modelling, we predicted that the catalytic Cys145 makes a nucleophilic attack on the carbonyl carbon of the cyclic ester common to both inhibitors, forming a stably acyl-enzyme complex. The computational and kinetic analyses confirm the formation of a stable acyl-enzyme complex with 3CL^pro. The results obtained enrich the knowledge of the already numerous biological activities exhibited by lichen secondary metabolites, paving the way for developing promising scaffolds for the design of cysteine enzyme inhibitors. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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16 pages, 1889 KiB

Open AccessArticle

Inhibition of Human Respiratory Influenza A Virus and Human Betacoronavirus-1 by the Blend of Double-Standardized Extracts of Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L.

by Michał Ochnik, Dominika Franz, Maciej Sobczyński, Piotr Naporowski, Mariusz Banach, Beata Orzechowska and Marta Sochocka

Pharmaceuticals 2022, 15(5), 619; https://doi.org/10.3390/ph15050619 - 17 May 2022

Cited by 9 | Viewed by 2893

Abstract

Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with [...] Read more.

Viral and bacterial diseases are among the greatest concerns of humankind since ancient times. Despite tremendous pharmacological progress, there is still a need to search for new drugs that could treat or support the healing processes. A rich source of bioactive compounds with antiviral potency include plants such as black chokeberry and elderberry. The aim of this study was to assess the in vitro antiviral ability of an originally designed double-standardized blend of extracts from Aronia melanocarpa (Michx.) Elliot and Sambucus nigra L. (EAM-ESN) or separated extracts of A. melanocarpa (EAM) or S. nigra (ESN) against four human respiratory tract viruses: influenza A virus (A/H1N1), betacoronavirus-1 (HCoV-OC43) belonging to the same β-coronaviruses as the current pandemic SARS-CoV-2, human herpesvirus type 1 (HHV-1), and human adenovirus type 5 (HAdV-5). Antiviral assays (AVAs) were used to evaluate the antiviral activity of the plant extracts in a cell-present environment with extracts tested before, simultaneously, or after viral infection. The virus replication was assessed using the CPE scale or luminescent assay. The EAM-ESN blend strongly inhibited A/H1N1 replication as well as HCoV-OC43, while having a limited effect against HHV-1 and HAdV-5. This activity likely depends mostly on the presence of the extract of S. nigra. However, the EAM-ESN blend possesses more effective inhibitory activity toward virus replication than its constituent extracts. A post-infection mechanism of action of the EAM-ESN make this blend the most relevant for potential drugs and supportive treatments; thus, the EAM-ESN blend might be considered as a natural remedy in mild, seasonal respiratory viral infections. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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19 pages, 8738 KiB

Open AccessEditor’s ChoiceArticle

In Silico and In Vitro Identification of Pan-Coronaviral Main Protease Inhibitors from a Large Natural Product Library

by Nasim Shahhamzehei, Sara Abdelfatah and Thomas Efferth

Pharmaceuticals 2022, 15(3), 308; https://doi.org/10.3390/ph15030308 - 3 Mar 2022

Cited by 31 | Viewed by 7904

Abstract

The main protease (M^pro or 3CL^pro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In [...] Read more.

The main protease (M^pro or 3CL^pro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In this study, we explored potential natural pan-coronavirus drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment targets. The PyRx program was used to screen 39,442 natural-product-like compounds from the ZINC database and 121 preselected phytochemicals from medicinal plants with known antiviral activity. After assessment with Lipinski’s rule of five, molecular docking was performed for the top 33 compounds of both libraries. Enzymatic assays were applied for the top candidates from both in silico approaches to test their ability to inhibit SARS-CoV-2 M^pro. The four compounds (hypericin, rosmarinic acid, isorhamnetin, and luteolin) that most efficiently inhibited SARS-CoV-2 M^pro in vitro were further tested for their efficacy in inhibiting M^pro of SARS-CoV-1 and MERS-CoV. Microscale thermophoresis was performed to determine dissociation constant (Kd) values to validate the binding of these active compounds to recombinant M^pro proteins of SARS-CoV-2, SARS-CoV-1, and MERS-CoV. The cytotoxicity of hypericin, rosmarinic acid, isorhamnetin, and luteolin was assessed in human diploid MRC-5 lung fibroblasts using the resazurin cell viability assay to determine their therapeutic indices. Sequence alignment of M^pro of SARS-CoV-2 demonstrated 96.08%, 50.83%, 49.17%, 48.51%, 44.04%, and 41.06% similarity to M^pro of other human-pathogenic coronaviruses (SARS-CoV-1, MERS-CoV, HCoV-NL63, HCoV-OC43, HCoV-HKU1, and HCoV-229E, respectively). Molecular docking showed that 12 out of 121 compounds were bound to SARS-CoV-2 M^pro at the same binding site as the control inhibitor, GC376. Enzyme inhibition assays revealed that hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited M^pro of SARS-CoV-2, while hypericin and isorhamnetin inhibited M^pro of SARS-CoV-1; hypericin showed inhibitory effects toward M^pro of MERS-CoV. Microscale thermophoresis confirmed the binding of these compounds to M^pro with high affinity. Resazurin assays showed that rosmarinic acid and luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin were slightly cytotoxic. We demonstrated that hypericin represents a potential novel pan-anti-coronaviral agent by binding to and inhibiting M^pro of several human-pathogenic coronaviruses. Moreover, isorhamnetin showed inhibitory effects toward SARS-CoV-2 and SARS-CoV-1 M^pro, indicating that this compound may have some pan-coronaviral potential. Luteolin had inhibitory effects against SARS-CoV-2 M^pro. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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14 pages, 2602 KiB

Open AccessArticle

Antiviral Effects of Artemisinin and Its Derivatives against SARS-CoV-2 Main Protease: Computational Evidences and Interactions with ACE2 Allelic Variants

by Riadh Badraoui, Mongi Saoudi, Walid S. Hamadou, Salem Elkahoui, Arif J. Siddiqui, Jahoor M. Alam, Arshad Jamal, Mohd Adnan, Abdel M. E. Suliemen, Mousa M. Alreshidi, Dharmendra K. Yadav, Houcine Naïli and Hmed Ben-Nasr

Pharmaceuticals 2022, 15(2), 129; https://doi.org/10.3390/ph15020129 - 22 Jan 2022

Cited by 30 | Viewed by 5189

Abstract

Fighting against the emergent coronavirus disease (COVID-19) remains a big challenge at the front of the world communities. Recent research has outlined the potential of various medicinal herbs to counteract the infection. This study aimed to evaluate the interaction of artemisinin, a sesquiterpene [...] Read more.

Fighting against the emergent coronavirus disease (COVID-19) remains a big challenge at the front of the world communities. Recent research has outlined the potential of various medicinal herbs to counteract the infection. This study aimed to evaluate the interaction of artemisinin, a sesquiterpene lactone extracted from the Artemisia genus, and its derivatives with the SARS-CoV-2 main protease. To assess their potential use against COVID-19, the interactions of the main active principle of Artemisia with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) was investigated through in silico probing. Our results showed that artemesinin and its derivatives manifested good oral absorption and bioavailability scores (0.55). They potently bound to the Mpro site of action—specifically, to its Cys145 residue. The selected compounds established two to three conventional hydrogen bonds with binding affinities ranging between −5.2 and −8.1 kcal/mol. Furthermore, artemisinin interactions with angiotensin converting enzyme 2 (ACE2) were dependent on the ACE2 allelic variants. The best score was recorded with rs961360700. A molecular dynamic simulation showed sufficient stability of the artemisinin–Mpro complex on the trajectory of 100 ns simulation frame. These binding interactions, together with drug-likeness and pharmacokinetic findings, confirmed that artemisinin might inhibit Mpro activity and explain the ethnopharmacological use of the herb and its possible antiviral activity against SARS-CoV-2 infection inducing COVID-19. Nevertheless, it interacted differently with the various ACE2 allelic variants reported to bind with the SARS-CoV-2 spike protein. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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22 pages, 4943 KiB

Open AccessArticle

Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71

by Jie Kai Tan, Ran Chen, Regina Ching Hua Lee, Feng Li, Kun Dai, Guo-Chun Zhou and Justin Jang Hann Chu

Pharmaceuticals 2022, 15(2), 115; https://doi.org/10.3390/ph15020115 - 18 Jan 2022

Cited by 5 | Viewed by 3882

Abstract

Hand-foot-and-mouth disease (HFMD) caused by human enterovirus A71 (EV-A71) infection has been associated with severe neurological complications. With the lack of an internationally approved antiviral, coupled with a surge in outbreaks globally, EV-A71 has emerged as a neurotropic virus of high clinical importance. [...] Read more.

Hand-foot-and-mouth disease (HFMD) caused by human enterovirus A71 (EV-A71) infection has been associated with severe neurological complications. With the lack of an internationally approved antiviral, coupled with a surge in outbreaks globally, EV-A71 has emerged as a neurotropic virus of high clinical importance. Andrographolide has many pharmacological effects including antiviral activity and its derivative, andrographolide sulfonate, has been used in China clinically to treat EV-A71 infections. This study sought to identify novel andrographolide derivatives as EV-A71 inhibitors and elucidate their antiviral mode of action. Using an immunofluorescence-based phenotypic screen, we identified novel EV-A71 inhibitors from a 344-compound library of andrographolide derivatives and validated them with viral plaque assays. Among these hits, ZAF-47, a quinolinoxy-andrographolide, was selected for downstream mechanistic studies. It was found that ZAF-47 acts on EV-A71 post-entry stages and inhibits EV-A71 protein expression. Subsequent luciferase studies confirm that ZAF-47 targets EV-A71 genome RNA replication specifically. Unsuccessful attempts in generating resistant mutants led us to believe a host factor is likely to be involved which coincide with the finding that ZAF-47 exhibits broad-spectrum antiviral activity against other enteroviruses (CV-A16, CV-A6, Echo7, CV-B5, CV-A24 and EV-D68). Furthermore, ZAF-46 and ZAF-47, hits from the screen, were derivatives of the same series containing quinolinoxy and olefin modifications, suggesting that an andrographolide scaffold mounted with these unique moieties could be a potential anti-EV-A71/HFMD strategy. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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14 pages, 2490 KiB

Open AccessArticle

Elucidating the Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches

by Minjee Kim, Hanul Choi, Sumin Kim, Lin Woo Kang and Young Bong Kim

Pharmaceuticals 2021, 14(9), 880; https://doi.org/10.3390/ph14090880 - 30 Aug 2021

Cited by 9 | Viewed by 3442

Abstract

The influenza virus is a constantly evolving pathogen that challenges medical and public health systems. Traditionally, curcumin has been used to treat airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate common targets of curcumin and influenza infection and underlying mechanisms, we [...] Read more.

The influenza virus is a constantly evolving pathogen that challenges medical and public health systems. Traditionally, curcumin has been used to treat airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate common targets of curcumin and influenza infection and underlying mechanisms, we employed network pharmacology and molecular docking approaches and confirmed results using in vitro experiments. Biological targets of curcumin and influenza were collected, and potential targets were identified by constructing compound–disease target (C-D) and protein–protein interaction (PPI) networks. The ligand–target interaction was determined using the molecular docking method, and in vitro antiviral experiments and target confirmation were conducted to evaluate curcumin’s effects on influenza. Our network and pathway analyses implicated the four targets of AKT1, RELA, MAPK1, and TP53 that could be involved in the inhibitory effects of curcumin on influenza. The binding energy calculations of each ligand–target interaction in the molecular docking showed that curcumin bound to AKT1 with the highest affinity among the four targets. In vitro experiments, in which influenza virus-infected MDCK cells were pre-, co-, or post-treated with curcumin, confirmed curcumin’s prophylactic and therapeutic effects. Influenza virus induction increased the level of mRNA expression of AKT in MDCK cells, and the level was attenuated by curcumin treatment. Collectively, our findings identified potential targets of curcumin against influenza and suggest curcumin as a potential therapy for influenza infection. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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19 pages, 6772 KiB

Open AccessArticle

Reynoutria Rhizomes as a Natural Source of SARS-CoV-2 Mpro Inhibitors–Molecular Docking and In Vitro Study

by Izabela Nawrot-Hadzik, Mikolaj Zmudzinski, Adam Matkowski, Robert Preissner, Małgorzata Kęsik-Brodacka, Jakub Hadzik, Marcin Drag and Renata Abel

Pharmaceuticals 2021, 14(8), 742; https://doi.org/10.3390/ph14080742 - 29 Jul 2021

Cited by 32 | Viewed by 7417

Abstract

More than a year has passed since the world began to fight the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the Coronavirus disease 2019 (COVID-19) pandemic, and still it spreads around the world, mutating at the same time. One of [...] Read more.

More than a year has passed since the world began to fight the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the Coronavirus disease 2019 (COVID-19) pandemic, and still it spreads around the world, mutating at the same time. One of the sources of compounds with potential antiviral activity is Traditional Chinese Medicinal (TCM) plants used in China in the supportive treatment of COVID-19. Reynoutria japonica is important part of the Shu Feng Jie Du Granule/Capsule-TCM herbal formula, recommended by China Food and Drug Administration (CFDA) for treatment of patients with H1N1- and H5N9-induced acute lung injury and is also used in China to treat COVID-19, mainly combined with other remedies. In our study, 25 compounds from rhizomes of R. japonica and Reynoutria sachalinensis (related species), were docked into the binding site of SARS-CoV-2 main protease. Next, 11 of them (vanicoside A, vanicoside B, resveratrol, piceid, emodin, epicatechin, epicatechin gallate, epigallocatechin gallate, procyanidin B2, procyanidin C1, procyanidin B2 3,3’-di-O-gallate) as well as extracts and fractions from rhizomes of R. japonica and R. sachalinensis were tested in vitro using a fluorescent peptide substrate. Among the tested phytochemicals the best results were achieved for vanicoside A and vanicoside B with moderate inhibition of SARS-CoV-2 Mpro, IC₅₀ = 23.10 µM and 43.59 µM, respectively. The butanol fractions of plants showed the strongest inhibition of SARS-CoV-2 Mpro (IC₅₀ = 4.031 µg/mL for R. sachalinensis and IC₅₀ = 7.877 µg/mL for R. japonica). As the main constituents of butanol fractions, besides the phenylpropanoid disaccharide esters (e.g., vanicosides), are highly polymerized procyanidins, we suppose that they could be responsible for their strong inhibitory properties. As inhibition of SARS-CoV-2 main protease could prevent the replication of the virus our research provides data that may explain the beneficial effects of R. japonica on COVID-19 and identify the most active compounds worthy of more extensive research. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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22 pages, 3416 KiB

Open AccessArticle

Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

by Yu-Chi Tsai, Racheal A. Nell, Jonathan E. Buckendorf, Norbert Kúsz, Peter Waweru Mwangi, Róbert Berkecz, Dóra Rédei, Andrea Vasas, Adam M. Spivak and Judit Hohmann

Pharmaceuticals 2021, 14(7), 653; https://doi.org/10.3390/ph14070653 - 7 Jul 2021

Cited by 5 | Viewed by 3347

Abstract

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the [...] Read more.

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (1–9, 14–17, 19, and 20) along with 16 known compounds from E. usambarica with HIV-1 latency reversal activity. Euphordraculoate C (1) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (2) and B (3) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4β-Crotignoid K (14) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (13), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids 12–14 and 21 for the HIV-1 latency reversal activity was activation of PKC, while lignans 26 and 27 that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from E. usambarica have the potential to contribute to the development of HIV-1 eradication strategies. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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Review

Jump to: Research, Other

19 pages, 1461 KiB

Open AccessReview

Pharmacological Potential of Flavonoids against Neurotropic Viruses

by Juliana Helena Castro e Silva, Jéssica Teles Souza, Clarissa Schitine, Aníbal de Freitas Santos Júnior, Eduardo Muniz Santana Bastos and Silvia Lima Costa

Pharmaceuticals 2022, 15(9), 1149; https://doi.org/10.3390/ph15091149 - 15 Sep 2022

Cited by 7 | Viewed by 2911

Abstract

Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed [...] Read more.

Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed to investigate the pharmacological potential of flavonoids in the face of viruses that can affect the central nervous system (CNS). We carried out research from 2011 to 2021 using the Pubmed platform. The following were excluded: articles not in the English language, letters to editors, review articles and papers that did not include any experimental or clinical tests, and papers that showed antiviral activities against viruses that do not infect human beings. The inclusion criteria were in silico predictions and preclinical pharmacological studies, in vitro, in vivo and ex vivo, and clinical studies with flavonoids, flavonoid fractions and extracts that were active against neurotropic viruses. The search resulted in 205 articles that were sorted per virus type and discussed, considering the most cited antiviral activities. Our investigation shows the latest relevant data about flavonoids that have presented a wide range of actions against viruses that affect the CNS, mainly influenza, hepatitis C and others, such as the coronavirus, enterovirus, and arbovirus. Considering that these molecules present well-known anti-inflammatory and neuroprotective activities, using flavonoids that have demonstrated both neuroprotective and antiviral effects could be viewed as an alternative for therapy in the course of CNS infections. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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20 pages, 1892 KiB

Open AccessEditor’s ChoiceReview

Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks

by Vincenzo Sorrenti, Francesca Benedetti, Alessandro Buriani, Stefano Fortinguerra, Giada Caudullo, Sergio Davinelli, Davide Zella and Giovanni Scapagnini

Pharmaceuticals 2022, 15(8), 912; https://doi.org/10.3390/ph15080912 - 23 Jul 2022

Cited by 23 | Viewed by 8796

Abstract

Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence [...] Read more.

Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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20 pages, 987 KiB

Open AccessReview

Utilization of Aloe Compounds in Combatting Viral Diseases

by Erica Españo, Jiyeon Kim and Jeong-Ki Kim

Pharmaceuticals 2022, 15(5), 599; https://doi.org/10.3390/ph15050599 - 13 May 2022

Cited by 14 | Viewed by 4994

Abstract

Plants contain underutilized resources of compounds that can be employed to combat viral diseases. Aloe vera (L.) Burm. f. (syn. Aloe barbadensis Mill.) has a long history of use in traditional medicine, and A. vera extracts have been reported to possess a huge [...] Read more.

Plants contain underutilized resources of compounds that can be employed to combat viral diseases. Aloe vera (L.) Burm. f. (syn. Aloe barbadensis Mill.) has a long history of use in traditional medicine, and A. vera extracts have been reported to possess a huge breadth of pharmacological activities. Here, we discuss the potential of A. vera compounds as antivirals and immunomodulators for the treatment of viral diseases. In particular, we highlight the use of aloe emodin and acemannan as lead compounds that should be considered for further development in the management and prevention of viral diseases. Given the immunomodulatory capacity of A. vera compounds, especially those found in Aloe gel, we also put forward the idea that these compounds should be considered as adjuvants for viral vaccines. Lastly, we present some of the current limitations to the clinical applications of compounds from Aloe, especially from A. vera. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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20 pages, 5024 KiB

Open AccessEditor’s ChoiceReview

Antiviral Activities of Andrographolide and Its Derivatives: Mechanism of Action and Delivery System

by Sya’ban Putra Adiguna, Jonathan Ardhianto Panggabean, Akhirta Atikana, Febriana Untari, Fauzia Izzati, Asep Bayu, A’liyatur Rosyidah, Siti Irma Rahmawati and Masteria Yunovilsa Putra

Pharmaceuticals 2021, 14(11), 1102; https://doi.org/10.3390/ph14111102 - 28 Oct 2021

Cited by 30 | Viewed by 10168

Abstract

Andrographispaniculata (Burm.f.) Nees has been used as a traditional medicine in Asian countries, especially China, India, Vietnam, Malaysia, and Indonesia. This herbaceous plant extract contains active compounds with multiple biological activities against various diseases, including the flu, colds, fever, diabetes, hypertension, and [...] Read more.

Andrographispaniculata (Burm.f.) Nees has been used as a traditional medicine in Asian countries, especially China, India, Vietnam, Malaysia, and Indonesia. This herbaceous plant extract contains active compounds with multiple biological activities against various diseases, including the flu, colds, fever, diabetes, hypertension, and cancer. Several isolated compounds from A. paniculata, such as andrographolide and its analogs, have attracted much interest for their potential treatment against several virus infections, including SARS-CoV-2. The mechanisms of action in inhibiting viral infections can be categorized into several types, including regulating the viral entry stage, gene replication, and the formation of mature functional proteins. The efficacy of andrographolide as an antiviral candidate was further investigated since the phytoconstituents of A. paniculata exhibit various physicochemical characteristics, including low solubility and low bioavailability. A discussion on the delivery systems of these active compounds could accelerate their development for commercial applications as antiviral drugs. This study critically reviewed the current antiviral development based on andrographolide and its derivative compounds, especially on their mechanism of action as antiviral drugs and drug delivery systems. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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23 pages, 869 KiB

Open AccessReview

Plant-Derived Antimicrobial Peptides as Potential Antiviral Agents in Systemic Viral Infections

by Nour Mammari, Ysaline Krier, Quentin Albert, Marc Devocelle, Mihayl Varbanov and on behalf of the OEMONOM

Pharmaceuticals 2021, 14(8), 774; https://doi.org/10.3390/ph14080774 - 6 Aug 2021

Cited by 22 | Viewed by 6443

Abstract

Numerous studies have led to a better understanding of the mechanisms of action of viruses in systemic infections for the development of prevention strategies and very promising antiviral therapies. Viruses still remain one of the main causes of human diseases, mainly because the [...] Read more.

Numerous studies have led to a better understanding of the mechanisms of action of viruses in systemic infections for the development of prevention strategies and very promising antiviral therapies. Viruses still remain one of the main causes of human diseases, mainly because the development of new vaccines is usually challenging and drug resistance has become an increasing concern in recent decades. Therefore, the development of potential antiviral agents remains crucial and is an unmet clinical need. One abundant source of potential therapeutic molecules are plants: they biosynthesize a myriad of compounds, including peptides which can have antimicrobial activity. Our objective is to summarize the literature on peptides with antiviral properties derived from plants and to identify key features of these peptides and their application in systemic viral infections. This literature review highlights studies including clinical trials which demonstrated that plant cyclotides have the ability to inhibit the growth of viruses causing human diseases, defensin-like peptides possess anti-HIV-1 activity, and lipid transfer proteins and some lectins exhibit a varied antimicrobial profile. To conclude, plant peptides remain interesting to explore in the context of emerging and re-emerging infectious diseases. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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19 pages, 2835 KiB

Open AccessSystematic Review

An Evaluation of the Potential of Essential Oils against SARS-CoV-2 from In Silico Studies through the Systematic Review Using a Chemometric Approach

by Luiz Torres Neto, Maria Lúcia Guerra Monteiro, Diego Galvan and Carlos Adam Conte-Junior

Pharmaceuticals 2021, 14(11), 1138; https://doi.org/10.3390/ph14111138 - 10 Nov 2021

Cited by 16 | Viewed by 4418

Abstract

Essential oils (EOs) and their compounds have attracted particular attention for their reported beneficial properties, especially their antiviral potential. However, data regarding their anti-SARS-CoV-2 potential are scarce in the literature. Thus, this study aimed to identify the most promising EO compounds against SARS-CoV-2 [...] Read more.

Essential oils (EOs) and their compounds have attracted particular attention for their reported beneficial properties, especially their antiviral potential. However, data regarding their anti-SARS-CoV-2 potential are scarce in the literature. Thus, this study aimed to identify the most promising EO compounds against SARS-CoV-2 based on their physicochemical, pharmacokinetic, and toxicity properties. A systematic literature search retrieved 1669 articles; 40 met the eligibility criteria, and 35 were eligible for analysis. These studies resulted in 465 EO compounds evaluated against 11 human and/or SARS-CoV-2 target proteins. Ninety-four EO compounds and seven reference drugs were clustered by the highest predicted binding affinity. Furthermore, 41 EO compounds showed suitable drug-likeness and bioactivity score indices (≥0.67). Among these EO compounds, 15 were considered the most promising against SARS-CoV-2 with the ADME/T index ranging from 0.86 to 0.81. Some plant species were identified as EO potential sources with anti-SARS-CoV-2 activity, such as Melissa officinalis Arcang, Zataria multiflora Boiss, Eugenia brasiliensis Cambess, Zingiber zerumbet Triboun & K.Larsen, Cedrus libani A.Rich, and Vetiveria zizanoides Nash. Our work can help fill the gap in the literature and guide further in vitro and in vivo studies, intending to optimize the finding of effective EOs against COVID-19. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)

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