Potential Antiviral Agents Research Articles

Development of Imidazo[1,2-a]pyridines Containing Sulfonyl Piperazines as Potential Antivirals against Tomato Spotted Wilt Virus.

Mesoionic structures have become important advancements in recent agrochemical design. However, their potential beyond serving as excellent insecticides remains unexplored with limited reports available. Herein, a series of imidazo[1,2-a]pyridine mesoionics were developed by structurally incorporating sulfonyl piperazine moieties into imidazo[1,2-a]pyridines. Many of the obtained derivatives demonstrated bioactivity against tomato spotted wilt virus (TSWV) in bioassays. In particular, compound Z40, identified via three-dimensional quantitative structure activity relation models, displayed encouraging protective performance (half-maximal effect concentration = 252 μg/mL) compared to the positive controls ningnanmycin (332 μg/mL) and vanisulfane (523 μg/mL). Through defense enzyme assays, real-time quantitative polymerase chain reaction, and proteomics analysis, Z40 was identified as a plant immunomodulator that promotes defense enzyme activity and the mediates oxidative phosphorylation pathway, enabling plants to resist TSWV. We expect this study to help expand the possibilities of mesoionic compounds.

Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells

Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions.Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model.Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches.In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.

Efficacy of CP-COV03 (a niclosamide-based inorganic nanohybrid product) against severe fever with thrombocytopenia syndrome virus in an in vitro model.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). CP-COV03 is a novel antiviral candidate that significantly enhanced the bioavailability of niclosamide through inorganic-based drug delivery technology. The active pharmaceutical ingredient of CP-COV03, niclosamide, has been previously shown to possess broad-spectrum antiviral activity against over 30 different viruses in the in vitro tests. The aim of this study is to confirm the antiviral activity of CP-COV03 against the SFTSV in an in vitro model. Vero cells and SFTS viral stock NCCP43270, a 2015 Gangwon Province isolate, were used to obtain the 50% tissue culture infective dose of the virus. Vero cells seeded in 96-well plates were infected with SFTSV for 1 h. SFTSV-infected cells were treated with CP-COV03 at various concentrations of 0.1-100 μM and incubated for 7 days. On the seventh day of the culture, the cytopathic effect (CPE) of SFTSV was checked by microscopy and the cell viability was checked by using Cell Counting Kit-8 assay. The CPE reduced as the CP-COV03 concentration increased. The 50% inhibitory concentration (IC50) range of CP-COV03 was below 0.125 µM, as determined from the viral titers of culture supernatants collected on the third day posttreatment of CP-COV03. The plaque reduction assay showed that the IC50 of CP-COV03 was 1.893 µM, as determined from the percentage reduction of plaque counts for each drug concentration on the second day posttreatment with CP-COV03. This study suggests that CP-COV03 could be used as a potential antiviral agent for SFTS.IMPORTANCEWe demonstrated a concentration-dependent response and identified low a IC50 of CP-COV03. This result is comparable to other antiviral drugs used against viruses like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We believe that our study makes a significant contribution to the literature as our findings suggest that CP-COV03 may serve as a potential treatment for SFTS, highlighting its importance in the field of antiviral research.

In silico investigation of therapeutic potential of phytosteroids against SARS-CoV2 infection via inhibition of viral multiplication and attenuation of host cytokine storm

SARS-CoV2 infection overcomes host cell membrane barrier, followed by utilization of host cellular processes for viral multiplication. Simultaneously, it triggers a cytokine storm within and around infected cells and tissues. Anti-inflammatory agents that can potentially inhibit viral penetration and multiplication within the host cells may be ideal drug candidates against COVID-19. Dietary phytosteroids have significant anti-inflammatory potential. Hence, the present study intends to investigate anti-viral potential of three dietary phytosteroids, namely, brassinolide, 28-homocastasterone and 24-epibrassinolide against SARS-CoV2 proteins, S1 spike protein, nucleocapsid protein and main protease enzyme, in addition to host pro-inflammatory proteins, interleukin-1, tumour necrosis factor-α, cyclooxygenase-2 and prostaglandin synthase, as drug targets. Molecular docking studies by AutoDock version 4.0 was performed. Brassinolide, 28-homocastasterone and 24-epibrassinolide exhibits high docking score against all the seven proteins, as compared to hydroxychloroquine. Brassinolide and 28- homocastasterone has maximum binding affinity for pro-inflammatory proteins and SARS-CoV2 proteins.Dietary phytosteroids may potentially attenuate cytokine storm with simultaneous inhibition of host entry and multiplication of SARS-CoV2. In-vitro and in-vivo anti-viral studies of plant steroids may provide a clear path for the identification and development of novel drug candidates against COVID-19, that also provides evidence for the concept of reverse pharmacognosy.

Oxoammonium salts exert antiviral effects against coronavirus via denaturation of their spike proteins

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) infection has forced social changes worldwide. Development of potent antiviral agents is necessary to prevent future pandemics. Titanium oxide, a photocatalyst, is a long-acting antiviral agent; however, its effects are weakened in the dark. Therefore, new antiviral substances that can be used in the dark are needed. Two types of nitroxyl radicals, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) and 2-azaadamantane N-oxyl (AZADO), are commonly used as oxidation catalysts utilizing oxygen in the air as the terminal oxidant. Therefore, in this study, we aimed to evaluate the potential of these radicals as antiviral compounds with sustained activity even in the dark. We evaluated the antiviral effects of oxoammonium salts corresponding to TEMPO and AZADO (TEMPO-Oxo and AZADO-Oxo, respectively), which are the active forms of nitroxyl radicals in oxidation reactions. TEMPO-Oxo and AZADO-Oxo inhibited the binding of SARS-CoV2 spike protein receptor-binding domain (S-RBD) to angiotensin-converting enzyme 2. Notably, AZADO-Oxo exhibited a 10-fold stronger inhibitory effect than TEMPO-Oxo. TEMPO-Oxo and AZADO-Oxo also denatured S-RBD; however, effects of AZADO-Oxo were 10-fold stronger than those of TEMPO-Oxo and did not change in the dark. Some S-RBD peptides treated with AZADO-Oxo were cleaved at the N-terminal side of tyrosine residues. TEMPO-Oxo and AZADO-Oxo exhibited concentration-dependent antiviral effects against feline coronavirus. In conclusion, active forms of the nitroxyl radicals, TEMPO-Oxo and AZADO-Oxo, exerted antiviral effects by denaturing S-RBD, regardless of the presence or absence of light, suggesting their potential as novel antiviral agents.

A synthetic curcumin-like diarylpentanoid analog inhibits rhinovirus infection in H1 hela cells via multiple antiviral mechanisms.

Rhinovirus (RV) infection is a major cause of common colds and asthma exacerbations, with no antiviral drug available. Curcumin exhibits broad-spectrum antiviral activities, but its therapeutic effect is limited by a poor pharmacokinetics profile. Curcumin-like diarylpentanoid analogs, particularly 2-benzoyl-6-(3,4-dihydroxybenzylidene)cyclohexen-1-ol (BDHBC) and 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), have better solubility and stability compared to curcumin. Therefore, this study aims to evaluate and compare the antiviral effects of curcumin, BDHBC, and DHHPD in an in vitro model of RV infection. The inhibitory effects on RV-16 infection in H1 HeLa cells were assessed using cytopathic effect (CPE) reduction assay, virus yield reduction assay, RT-qPCR, and Western blot. Antiviral effects in different modes of treatment (pre-, co-, and post-treatment) were also compared. Additionally, intercellular adhesion molecule 1 (ICAM-1) expression, RV binding, and infectivity were measured with Western blot, flow cytometry, and virucidal assay, respectively. When used as a post-treatment, BDHBC (EC50: 4.19µM; SI: 8.32) demonstrated stronger antiviral potential on RV-16 compared to DHHPD (EC50: 18.24µM; SI: 1.82) and curcumin (less than 50% inhibition). BDHBC also showed the strongest inhibitory effect on RV-induced CPE, virus yield, vRNA, and viral proteins (P1, VP0, and VP2). Furthermore, BDHBC pre-treatment has a prophylactic effect against RV infection, which was attributed to reduced basal expression of ICAM-1. However, it did not affect virus binding, but exerted virucidal activity on RV-16, contributing to its antiviral effect during co-treatment. BDHBC exhibits multiple antiviral mechanisms against RV infection and thus could be a potential antiviral agent for RV.

Chemical synthesis of a trisaccharide fragment of a fucosylated glucuronomannan isolated from brown algae

Fucose is abundant in marine organisms, primarily as fucoidan and fucosylated chondroitin sulfate. Our previous study characterized a sulfated and fucosylated glucuronomannan (SFGM) isolated from marine brown algae, exhibiting notable antiviral activity and potential for drug development. Herein, a trisaccharide fragment of this SFGM in the form of [α-L-Fuc(2, 4-diS)]-(1→3)-α-D-Man-(1→4)-α-D-GlcA-OMP was synthesized for the first time. Stereoselective formation of the α-1,2-cis-fucosidic bond was achieved by leveraging solvent effects. The sulfated trisaccharide as the final product, featuring a 2,4-diS-fucose unit and the p-methoxyphenyl group as a pendant at the anomeric position, was successfully accomplished. The synthetic strategy developed in this study offers a foundation for the pharmaceutical development of these SFGM oligosaccharides.

Integrative in silico evaluation of the antiviral potential of terpenoids and its metal complexes derived from Homalomena aromatica based on main protease of SARS-CoV-2

Abstract Substantial research is currently conducted focusing on the development of promising antiviral drugs employing in silico screening and drug repurposing strategies against SARS-CoV-2. The current study aims at identifying lead molecules targeting SARS-CoV-2 by the application of in silico and molecular dynamics (MD) approaches from phytoconstituents present in Homalomena aromatica. The main protease (Mpro) enzyme of SARS-CoV-2 is taken as the target protein to perform the docking analysis of 71 molecules reported from H. aromatica by the application of different modules of Discovery Studio 2018. Five molecules were taken as prospective leads namely dihydrocuminaldehyde, p-cymen-8-ol, cuminaldehyde, p-cymene, and cuminol. In the absence of known inhibitors, a comparative study was performed with the compounds reported in the literature and potent terpenoid–metal complexes were taken into account based on known efficacy as anti-viral molecules. After performing the docking studies with Mpro enzyme of SARS-CoV-2, it was observed that the –CDocker Energy of cuminaldehyde thiosemicarbazone was 29.152, indicating a significant affinity toward Mpro. The same was also supported by the MD study. Taken together, our results provided in silico evidence that secondary metabolites derived from H. aromatica could be employed as potent antiviral agents targeting SARS-CoV-2. Our findings warrant further validation of their in vitro and in vivo efficacies prior to their development into bona fide therapeutic agents.

Assessing biochar, clinoptilolite zeolite and zeo-char loaded nano-nitrogen for boosting growth performance and biochemical ingredients of peace lily (Spathiphyllum Wallisii) plant under water shortage

BackgroundPeace lily (Spathiphyllum wallisii Regel) is an ornamental indoor plant with promising cut flower market, as well as antiviral, pharmacological and ecological potentials. Water deficiency can have sound effects on the growth performance and aesthetic quality of such plant. The aim of this study was to investigate the consequences of zeolite, biochar, and zeo-char loaded nano-nitrogen application on the growth performance and biochemical components of peace lily under water shortage conditions. An experiment was conducted over two consecutive seasons (2021–2022) at the experimental nursery of Ornamental Horticulture Department, Faculty of Agriculture, Cairo University, Giza, Egypt. Soil amendments; zeolite, biochar, and zeo-char loaded nano-nitrogen were prepared and applied to soil before cultivation.ResultsOur results revealed that the new combination treatment (zeo-char loaded nano-N) had an exceeding significant effect on most of the studied parameters. Vegetative traits such as plant height (35.7 and 35.9%), leaf number per plant (73.3 and 52.6%), leaf area (40.2 and 36.4%), stem diameter (28.7 and 27.1%), root number (100 and 43.5%) and length (105.7 and 101.9%) per plant, and fresh weight of leaves (23.2 and 21.6%) were significantly higher than control (commercially recommended dose of NPK) with the application of zeo-char loaded nano-N during the two growing seasons, respectively. Similar significant increments were obtained for some macro- (N, P, K, Mg, Ca) and micro- (Fe, Zn, Mn) elements with the same treatment relative to control. Chlorophyll (18.4%) and total carotenoids (82.9 and 32.6%), total carbohydrates (53.3 and 37.4%), phenolics (54.4 and 86.9%), flavonoids (31.7% and 41.8%) and tannins (69.2 and 50%), in addition to the phytohormone gibberellic acid (GA3) followed the same trend with the application of zeo-char loaded nano-N, increasing significantly over control. Leaf histological parameters and anatomical structure were enhanced with the new combination treatment in comparison with control. Antioxidant enzymes (catalase and peroxidase), proline and abscisic acid (ABA) exhibited significant declines with zeo-char loaded nano-N treatment relative to control.ConclusionThese findings suggest that incorporating soil amendments with nano- nutrients could provide a promising approach towards improving growth performance and quality of ornamental, medicinal and aromatic species under water deficiency conditions.

Antioxidant, Anti-inflammatory, Antiviral and Anticancer Potentials of Zingiberaceae Species Used as Herbal Medicine in Indonesia

Antioxidant, Anti-inflammatory, Antiviral and Anticancer Potentials of Zingiberaceae Species Used as Herbal Medicine in Indonesia

Evaluation of Thiazolidine Derivatives with Potential Anti-ZIKV Activity.

In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects. Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus. Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5μM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site. The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.

Identification of nitrile-containing isoquinoline-related natural product derivatives as coronavirus entry inhibitors in silico and in vitro

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since its emergence in Wuhan, China, in late 2019. Natural product inhibitors targeting the interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (ACE2), crucial for viral attachment and cellular entry, are of significant interest as potential antiviral agents. In this study a library of nitrile- and sulfur-containing natural product derived compounds were used for virtual drug screening against the RBD of the SARS-CoV-2 spike protein. The top 18 compounds from docking were tested for their efficacy to inhibit virus entry. In vitro experiments revealed that compounds 9, 14, and 15 inhibited SARS-CoV-2 pseudovirus and live virus entry in HEK-ACE2 and Vero E6 host cells at low micromolar IC50 values. Cell viability assays showed these compounds exerted low cytotoxicity towards MRC5, Vero E6, and HEK-ACE2 cell lines. Microscale thermophoresis revealed all three compounds strongly bound to the RBDs of SARS-CoV-2, SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values increasing as RBD sequence similarity decreased. Molecular docking studies indicated compounds 9, 14, and 15 bound to the SARS-CoV-2 spike protein RBD and interacted with hotspot amino acid residues required for the RBD-ACE2 interaction and cellular infection. These three nitrile-containing candidates, particularly compound 15, should be considered for further development as potential pan-coronavirus entry inhibitors.

Antiviral effects of Sarcodia suae water extracts against vesicular stomatitis virus infection

ABSTRACT Marine algae, a rich source of bioactive substances, have long been utilized in biomedical and veterinary sciences. This study breaks new ground by assessing the antiviral therapeutic potential of water extracts from four algal species – Colaconema formosanum, Caulerpa microphysa, Gelidium amansii and Sarcodia suae – against vesicular stomatitis virus (VSV) infection. The standout among these was Sarcodia suae water extract (SSWE), which not only significantly repressed VSV replication and enhanced cell survival without cytotoxic effects, but also demonstrated its antiviral activity through interference with viral attachment, entry, RNA replication, and egress, and reduced VSV-induced autophagy in Mv1Lu cells during the late stages of infection. The EC50 of SSWE was 0.422 ± 0.14 mg ml‒1. The cytotoxicity assay confirmed the high biocompatibility of SSWE. This study identifies SSWE as a promising natural antiviral agent and elucidates its mechanisms of action, highlighting the need for further research to optimize its use in controlling VSV-related diseases.

Cholic acid-based inhibition of SVCV replication by modulating polyunsaturated fatty acid content

Spring Viremia of Carp Virus (SVCV) is a highly pathogenic pathogen that infects carp fish, and SVCV infection frequently causes a severe inflammatory response in the affected fish. The viral infection is extremely lethal in carp larvae, often leading to heavy economic losses. Cholic acid (CA) is a primary bile acid synthesized directly from cholesterol in the liver and has been found to have an inhibitory effect on viral infections. To substantiate this antiviral potential, 500 μM CA was tested against SVCV replication in vitro and showed a significant inhibitory effect on viral replication. Further experimental tests demonstrated that CA exerted antiviral effects during its replication phase but not at viral adsorption and entry stages. In vivo experiments demonstrated that CA increased the survival rate of SVCV-infected zebrafish by 40 %, reduced viral load in tissues and reduced histopathological lesions. Comparison of the liver transcriptome of zebrafish between CA treatment and control (NC) groups revealed that CA treatment was able to promote the synthesis of polyunsaturated fatty acids, with the most significant changes in docosahexaenoic acid (DHA). Inhibition assay on fatty acid desaturase 2 (Fads2), the first rate-limiting enzyme for the synthesis of polyunsaturated fatty acid, showed that the antiviral effect of CA on SVCV disappeared. These new findings suggest that CA may exert its antiviral effects by regulating the synthesis of polyunsaturated fatty acid. In addition, this study also verified that DHA has antiviral activity against SVCV. In conclusion, CA shows promise as a potential anti-SVCV drug or feed additive that could help mitigate SVCV outbreaks in aquaculture.

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

ABSTRACT Foot-and-Mouth Disease (FMD) is a contagious, blistering disease caused by the Foot-and-Mouth Disease virus (FMDV), which affects livestock globally. Currently, no commercial antiviral agent is available for effective disease control. This study investigated the antiviral potential of natural-derived alkaloids against FMDV in BHK-21 cells. Twelve alkaloids were assessed for their antiviral activities at various stages of FMDV infection, including pre-viral entry, post-viral entry, and prophylactic assays, as well as attachment and penetration assays by evaluating cytopathic effect reduction and directed-virucidal effects. The results showed that ipecac alkaloids, cephaeline (CPL) and emetine (EMT), exhibited dual effects with robust antiviral efficacy by reducing cytopathic effect and inhibiting FMDV replication in a dose-dependent manner. Evaluation through immunoperoxidase monolayer assay and RT-PCR indicated effectiveness at post-viral entry stage, with sub-micromolar EC50 values for CPL and EMT at 0.05 and 0.24 µM, respectively, and high selective indices. Prophylactic effects prevented infection with EC50 values of 0.23 and 0.64 µM, respectively. Directed-virucidal effects demonstrated significant reduction of extracellular FMDV, with CPL exhibiting a dose-dependent effect. Furthermore, the replicase (3Dpol) inhibition activity was identified using the FMDV minigenome assay, which revealed strong inhibition with IC50 values of 0.15 µM for CPL and 4.20 µM for EMT, consistent with the decreased negative-stranded RNA production. Molecular docking confirmed the interaction of CPL and EMT with residues in the active site of FMDV 3Dpol. In conclusion, CPL and EMT exhibited promising efficacy through their dual effects and provide an alternative approach for controlling FMD in livestock.

The Antiviral Potential of a Natural Compound for COVID-19: A Review of the Current Findings

Objective Coronavirus disease 2019 (COVID-19), a novel viral disease originating from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a life-threatening disease with dramatic morbidity and mortality globally. In this review, we aim to discuss the current evidence showing that the Imam Kazem drug, a natural compound that comprises Foeniculum vulgare, Terminalia chebula, Pistacia lentiscus, and red sugar, may be a therapeutic candidate in the fight against COVID-19 infection. Methods This literature review was performed by searching related words, including “ Imam Kazem drug,” “ Foeniculum vulgare,” “ Terminalia chebula,” “ Pistacia lentiscus,” “ Red sugar,” “Natural compounds,” “Traditional medicine,” “Coronaviruses,” “Antiviral,” “COVID-19,” “SARS-CoV-2,” in different databases like Google Scholar, Scopus, PubMed, Web of Science, and Scientific Information Databases until 2023. Results The current documents underscore that the Imam Kazem drug may be safe and effective against COVID-19. This natural compound, thanks to its constituents, may affect the pathogenic occurrence related to the disease, such as attenuating oxidative stress and inflammation-associated occurrences by different mechanisms, like scavenging free radicals, enhancing the function of antioxidant enzymes, and attenuating cytokine storm. Moreover, the Imam Kazem drug can exert its antiviral ability mainly by suppressing viral replication and blocking glycosaminoglycan binding sites. However, more preclinical and clinical evidence is required to support these results. Conclusion Imam Kazem drug may have a therapeutic capacity for patients with COVID-19 infection.

Development and characterization of formulations based on combinatorial potential of antivirals against genital herpes.

Herpes simplex virus type 2 (HSV-2) treatment faces challenges due to antiviral resistance and systemic side effects of oral therapies. Local delivery of antiviral agents, such as tenofovir (TDF) and zinc acetate dihydrate (ZAD), may offer improved efficacy and reduced systemic toxicity. This study's objective is to develop and evaluate local unit dose formulations of TDF and ZAD combination for local treatment of HSV-2 infection and exploring their individual and combinatory effects in vitro. The study involved the development of immediate-release film and pessary formulations containing TDF and ZAD. These formulations were characterized for physicochemical properties and in vitro drug release profiles. Cytotoxicity and antiviral activity assays were conducted to evaluate the individual and combinatory effects of TDF and ZAD. Film formulations released over 90% of the drugs within 1h, and pessary formulations within 90min, ensuring effective local drug delivery. ZAD showed moderate antiviral activity while TDF exhibited significant antiviral activity at non-cytotoxic concentrations. The combination of TDF and ZAD demonstrated synergistic effects in co-infection treatments, reducing the concentration required for 50% inhibition of HSV-2. Developed film and pessary formulations offer consistent and predictable local drug delivery, enhancing antiviral efficacy while minimizing systemic side effects. The combination of TDF and ZAD showed potential synergy against HSV-2, particularly in co-infection treatments. Further preclinical studies on pharmacokinetics, safety, and efficacy are necessary to advance these formulations toward clinical application.

Identification of steroidal cardenolides from Calotropis procera as novel HIV-1 PR inhibitors: A molecular docking & molecular dynamics simulation study.

Background & objectives Despite advancements in antiretroviral therapy, drug-resistant strains of HIV (human immunodeficiency virus) remain a global health concern. Natural compounds from medicinal plants offer a promising avenue for developing new HIV-1 PR (protease) inhibitors. This study aimed to explore the potential of compounds derived from Calotropis procera, a medicinal plant, as inhibitors of HIV-1 PR. Methods This in silico study utilized natural compound information and the crystal structure of HIV-1 PR. Molecular docking of 17 steroidal cardenolides from Calotropis procera against HIV-1 PR was performed using AutoDock 4.2 to identify compounds with higher antiviral potential. A dynamic simulation study was performed to provide insights into the stability, binding dynamics, and potential efficacy of the top potential antiviral compound as an HIV-1 therapeutic. Results We found that all tested cardenolides had higher binding affinities than Amprenavir, indicating their potential as potent HIV-1 PR inhibitors. Voruscharin and uscharidin displayed the strongest interactions, forming hydrogen bonds and hydrophobic interactions with HIV-1 PR. Voruscharin showed improved stability with lower RMSD (Root Mean Square Deviation) values and reduced fluctuations in binding site residues but increased flexibility in certain regions. The radius of gyration analysis confirmed a stable binding pose between HIV-1 PR and Voruscharin. Interpretation & conclusions These findings suggest that Calotropis procera could potentially be a source of compounds for developing novel HIV-1 PR inhibitors, contributing to the efforts to combat HIV. Further studies and clinical trials are needed to evaluate the safety and efficacy of these compounds as potential drug candidates for the treatment of HIV-1 infection.

Mechanism of non-competitive inhibition of the SARS-CoV-2 3CL protease dimerization: Therapeutic and clinical promise of the lichen secondary metabolite perlatolinic acid

In response to the COVID-19 pandemic, identifying effective treatments against SARS-CoV-2 has become of utmost importance. This study elucidates the mechanism by which perlatolinic acid, a lichen-derived secondary metabolite, non-competitively inhibits the dimerization of the SARS-CoV-2 3CL protease, a pivotal enzyme in the virus lifecycle. Utilising a combination of kinetic parameter determination, inhibition assays, and molecular docking studies, we demonstrate that perlatolinic acid effectively disrupts the enzymatic function by binding at the dimer interface with a measured Ki value of 0.67 μM, thereby impeding the protease catalytic activity essential for viral replication. Molecular docking studies further corroborate the binding specificity of perlatolinic acid to the dimer interface, which is attributed to the loss of key interactions essential for dimerization, consequently impairing catalytic activity, highlighting its potential as a scaffold for developing broad-spectrum antiviral drugs.Despite a dose-dependent cytotoxicity of perlatolinic acid, its TC50 is approximately 43 times higher than the Ki value.Our findings suggest that perlatolinic acid holds significant promise as a lead compound for the development of new therapeutics against COVID-19, warranting further investigation and clinical evaluation.In conclusion, the study sheds light on the therapeutic potential of natural compounds in combating SARS-CoV-2, paving the way for the exploration of lichen secondary metabolites as a reservoir of potential antiviral agents.

A broad-spectrum biological activities of Heracleum humile extracts: A first report of the antiviral, anti-cancer and chemical properties

The current work focused on researching the bioactive potential of ethyl acetate (EA), methanol (MeOH), and water extract of H. humile plant, specifically ethyl acetate, methanol extracts were acquired with maceration method, and water extract was obtained by the infusion method. The highest total phenolic ingredient was determined in the water extract, while the highest total flavonoid ingredient was found in the MeOH extract. The water extract displayed the most potent antioxidant activity in the assays used. The ethyl acetate extract showed the highest enzyme inhibition activity in Butyrylcholinesterase inhibition (BChE) and amylase assay. Antibacterial efficiency was analyzed using microdilution analysis. The minimum inhibitory concentration (MIC) amounts ranged from 125 to 500 μg/mL except for water extract. The antiviral potential of the extracts was assessed against Bovine herpes virus 1 (BoHV-1) (Cooper strain). Methanol extract showed more potent antiviral effect. Selectivity indices were calculated for ethyl acetate and methanol extract as 3.32 and 13.39, respectively. All extracts displayed Deoxyribonucleic Acid (DNA) protection activity at approximately 25%–35%. For cell viability evaluation, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test was performed against triple-negative human breast adenocarcinoma cells (MDA-MB-231) and Michigan Cancer Foundation-7 (MCF-7) cells. The most effective results were found in ethyl acetate extract at 48h. The 50% inhibitor concentrations (IC50) were determined for MDA-MB-231 and MCF-7 as 116.7 μg/mL and 247.9 μg/mL, respectively. Based on the bioactive compound content results, extracts of H. humile include valuable compounds that possess significant biological properties. In conclusion, these extracts could offer promising novel plant-derived therapeutics.