Anti-influenza Virus Agents Research Articles

Sesquiterpenoids from the roots and rhizomes of Valeriana officinalis var. latifolia

The genus Valeriana is used in traditional Chinese medicine to treat nervous disorders, sleep disorders, epilepsy and skin diseases. A large number of sesquiterpenoids from this genus have been found to exhibit anti-inflammatory, antiproliferative, anti-influenza virus and neuroprotective activities. In order to discover more sesquiterpenoids with structural diversity and bioactivity from Valeriana plants, fifteen sesquiterpenoids, including ten undescribed ones, valernaenes A−J (1, 5−7, 9−11 and 13−15), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated by extensive spectroscopic techniques (1D, 2D NMR and HRESIMS) and electronic circular dichroism (ECD) calculation. Structurally, valernaenes C (6) and D (7) were two caryophyllane-type norsesquiterpenoids. In addition, valernaenes A (1) and F (10) exhibited anti-influenza virus activity with EC50 values of 38.76 ± 1.44 and 23.01 ± 4.89 μM, respectively. Furthermore, caryophyllenol A (2) showed promoting effect on nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells with differentiation rate of 12.26% at a concentration of 10 μM. This study not only enriched the structural diversity of sesquiterpenoids in the genus Valeriana, but also provided theoretical basis for the discovery of anti-influenza virus and neuroprotective agents from this genus.

An N-terminal heptad repeat trimer-based peptide fusion inhibitor exhibits potent anti-H1N1 activity

Influenza viruses are susceptible to seasonal influenza, which has repeatedly caused global pandemics and jeopardized human health. Vaccines are only used as preventive medicine due to the extreme mutability of influenza viruses, and antiviral medication is the most significant clinical treatment to reduce influenza morbidity and mortality. Nevertheless, the clinical application of anti-influenza virus agents is characterized by the narrow therapeutic time window, the susceptibility to drug resistance, and relatively limited effect on severe influenza. Therefore, it is of great significance to develop novel anti-influenza virus drugs to fulfill the urgent clinical needs. Influenza viruses enter host cells through the hemagglutinin (HA) mediated membrane fusion process, and fusion inhibitors function antivirally by blocking hemagglutinin deformation, promising better therapeutic efficacy and resolving drug resistance, with targets different from marketed medicines. Previous studies have shown that unnatural peptides derived from Human Immunodeficiency Virus Type 1 (HIV-1) membrane fusion proteins exhibit anti-HIV-1 activity. Based on the similarity of the membrane fusion protein deformation process between HIV-1 and H1N1, we selected sequences derived from the gp41 subunit in the HIV-1 fusion protein, and then constructed N-trimer spatial structure through inter-helical isopeptide bond modification, to design the novel anti-H1N1 fusion inhibitors. The results showed that the novel peptides could block 6-HB formation during H1N1 membrane fusion procedure, and thus possessed significant anti-H1N1 activity, comparable to the positive control oseltamivir. Our study demonstrates the design viability of peptide fusion inhibitors based on similar membrane fusion processes among viruses, and furthermore provides an important idea for the novel anti-H1N1 inhibitors development.

Synthesis of Rupestonic Acid L-Ephedrine Derivatives with Preliminary In vitro Anti-influenza Viral Activity.

Influenza virus is a kind of RNA virus. Nowadays, the high incidence of influenza and the morbidity and mortality of epidemic influenza are substantial. It has been reported that one hundred million people in the world are infected with influenza viruses, and two hundred and fifty thousand to five hundred thousand people die from the flu per year. In 2021, the number of infected persons in China was reported to be 654,700, and 0.07% of the infected persons died. The flu has caused a serious threat to human survival. Although several drugs, such as Zanamivir, Oseltamivir, Peramivir, and Laninamivir, have been used in clinics for the treatment of the influenza virus, there are some shortcomings of these drugs. The strain of influenza H5N1 (avian influenza) has been found to resist the effective drug Oseltamivir. Thus, there is an urgent demand to discover new influenza virus inhibitors to overcome the emergence of influenza antigens. This study aimed to develop new influenza virus inhibitors based on the rupestonic acid parent core. The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized in this work for the development of influenza virus inhibitors. The target compounds were synthesized using rupestonic acid and L-ephedrine as starting materials. Their structures were characterized by 1H NMR and 13C NMR, and the purity was determined by HPLC. Then, their preliminary in vitro influenza activity was evaluated using Oseltamivir as a reference drug. The results showed that the synthesized rupestonic acid L-ephedrine derivatives A and B were more potent influenza virus inhibitors against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) with the IC50 values of 51.0, 51.0 μM and 441.0, 441.0 μM, respectively, than that of rupestonic acid. By comparing the IC50 of compounds A and B, compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized and characterized using 1H NMR and 13C NMR. Moreover, their purity was determined by HPLC. Both compounds A and B exhibited more potent activities against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) than rupestonic acid. Compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. Based on these results, more rupestonic acid derivatives will be designed and synthesized in the future for the development of influenza virus inhibitors.

High-Value-Added Utilization of Turpentine: Screening of Anti-Influenza Virus Agents from <i>β</i>-Pinene Derivatives

High-Value-Added Utilization of Turpentine: Screening of Anti-Influenza Virus Agents from <i>β</i>-Pinene Derivatives

Nitrostilbenes: Synthesis and Biological Evaluation as Potential Anti-Influenza Virus Agents.

Resveratrol (RSV) is a natural stilbene polyphenolic compound found in several plant species. It is characterized by antioxidant properties, and its role in controlling viral replication has been demonstrated for different viral infections. Despite its promising antiviral properties, RSV biological activity is limited by its low bioavailability and high metabolic rate. In this study, we optimized its structure by synthesizing new RSV derivatives that maintained the phenolic scaffold and contained different substitution patterns and evaluated their potential anti-influenza virus activity. The results showed that viral protein synthesis decreased 24 h post infection; particularly, the nitro-containing compounds strongly reduced viral replication. The molecules did not exert their antioxidant properties during infection; in fact, they were not able to rescue the virus-induced drop in GSH content or improve the antioxidant response mediated by the Nrf2 transcription factor and G6PD enzyme. Similar to what has already been reported for RSV, they interfered with the nuclear-cytoplasmic traffic of viral nucleoprotein, probably inhibiting cellular kinases involved in the regulation of specific steps of the virus life cycle. Overall, the data indicate that more lipophilic RSV derivatives have improved antiviral efficacy compared with RSV and open the way for new cell-targeted antiviral strategies.

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents.

In this study, a series of 4-[(quinolin-4-yl)amino]benzamide derivatives as the novel anti-influenza agents were designed and synthesized. Cytotoxicity assay, cytopathic effect assay and plaque inhibition assay were performed to evaluate the anti-influenza virus A/WSN/33 (H1N1) activity of the target compounds. The target compound G07 demonstrated significant anti-influenza virus A/WSN/33 (H1N1) activity both in cytopathic effect assay (EC50 = 11.38 ± 1.89 µM) and plaque inhibition assay (IC50 = 0.23 ± 0.15 µM). G07 also exhibited significant anti-influenza virus activities against other three different influenza virus strains A/PR/8 (H1N1), A/HK/68 (H3N2) and influenza B virus. According to the result of ribonucleoprotein reconstitution assay, G07 could interact well with ribonucleoprotein with an inhibition rate of 80.65% at 100 µM. Furthermore, G07 exhibited significant activity target PA−PB1 subunit of RNA polymerase according to the PA−PB1 inhibitory activity prediction by the best pharmacophore Hypo1. In addition, G07 was well drug-likeness based on the results of Lipinski’s rule and ADMET prediction. All the results proved that 4-[(quinolin-4-yl)amino]benzamide derivatives could generate potential candidates in discovery of anti-influenza virus agents.

Obat Herbal dari Akar Manis (Glycyrrhiza glabra L.) untuk Pencegahan dan Pengobatan Infeksi Virus H1N1, H5N1 dan COVID-19: Systematic Review

Herbs have been used as a form of traditional medicine since ancient times. Licorice is one of the herbs that has long been used as medicine. This plant contains different plant compounds, such as glycyrrhizin, 18??glycyrrhetinic acid, glabrins A and B, and isoflavones, showing various pharmacological activities. Pharmacological experiments have shown that different extracts and pure compounds of this species exhibit broad biological properties, including antibacterial, anti-inflammatory, antiviral, antioxidant, and antidiabetic activities. This systematic review aims to determine the effectiveness of herbal medicine from licorice (Glycyrrhiza glabra L.) to prevent and treat H1N1, H5N1, and COVID-19 virus infections from various previous research results. This research is a systematic review using the PRISMA method. A total of 8 articles that met the inclusion and exclusion criteria were continued for analysis. A total of 8 articles discuss the effectiveness of licorice on the H1N1, H5N1, and COVID-19 viruses. The articles used include articles published in national journals and international journals. The results showed that 1) Licorice root is effectively used for the prevention and treatment of H1N1, H5N1, and COVID-19 virus infections, 2) Glycyrrhizic acid (GA) is the main compound for the development of potential anti-influenza virus agents. Overall, it can be concluded that licorice and some of its derivatives have the potential as anti-influenza agents for H1N1, H5N1, and COVID-19.

Baloxavir Marboxil Polymorphs: Investigating the Influence of Molecule Packing on the Dissolution Behavior

Baloxavir marboxil (BXM) is a new blockbuster FDA-approved anti-influenza virus agent. However, its poor solubility has limited its oral bioavailability. In this study, BXM was crystallized from several organic solvents, obtaining three polymorphs, and their dissolution behaviors were studied. Detailed crystallographic examination revealed that Form I is monoclinic, space group P21, with unit cell parameters a = 7.1159 (3) Å, b = 20.1967 (8) Å, c = 9.4878 (4) Å, β = 109.033 (1)°, V = 1289.02 (9) Å3, and Z = 2, and Form II is monoclinic, space group P21, with unit cell parameters a = 7.1002 (14) Å, b = 39.310 (7) Å, c = 9.7808 (18) Å, β = 110.966 (5)°, V = 2549.2 (8) Å3, and Z = 4. Form I has a rectangular three-dimensional energy frameworks net, while Form II has a two-dimensional net. On the other hand, Form II has a much larger percentage of its surface area of exposed hydrogen bond acceptors than Form I. These crystallographic features offered increased solubility and dissolution rate to Form II. The results of stability and solubility experiments suggest that Form II may be preferred in the solid form used for the industrial preparation of BXM medicinal products.

The CDK1 inhibitor, Ro-3306, is a potential antiviral candidate against influenza virus infection

Many viruses use the host cell division cycle to facilitate replication. Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that play a central role in regulating cell cycle progression. However, the prospect of using CDKs for anti-influenza virus treatment remains to be elucidated. We conducted this study to investigate the potential of the CDK1 inhibitor Ro-3306 in preventing influenza virus infection and to elucidate the underlying mechanism. We showed that Ro-3306, a CDK1 inhibitor, exerts anti-influenza activity both in vitro and in vivo. Proof-of-concept studies revealed that knockdown of host CDK1 might affect the splicing of M2 viral mRNA, leading to the restriction of viral replication. Moreover, Ro-3306 directly bound to viral PB2 protein and inhibited viral RNA replication. Transcriptome analysis further revealed that Ro-3306 treatment inhibited the expression of MAPK-regulated genes, which might also contribute to the antiviral activity of Ro-3306. This study highlighted the multifunctional role of Ro-3306 as a novel anti-influenza virus agent.

Identification of Nifurtimox and Chrysin as Anti-Influenza Virus Agents by Clinical Transcriptome Signature Reversion.

The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to disease or compounds’ perturbations. Two compounds, nifurtimox and chrysin, were identified by a modified Kolmogorov–Smirnov test statistic based on the transcriptional signatures from 81 IAV-infected patients and the gene expression profiles of 1309 compounds. Their activities were verified in vitro with half maximal effective concentrations (EC50s) from 9.1 to 19.1 μM against H1N1 or H3N2. It also suggested that the two compounds interfered with multiple sessions in IAV infection by reversing the expression of 28 IAV informative genes. Through network-based analysis of the 28 reversed IAV informative genes, a strong synergistic effect of the two compounds was revealed, which was confirmed in vitro. By using the transcriptome signature reversion (TSR) on clinical datasets, this study provides an efficient scheme for the discovery of drugs targeting multiple host factors regarding clinical signs and symptoms, which may also confer an opportunity for decelerating drug-resistant variant emergence.

In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L.

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health. Isatis tinctoria L. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-based in silico framework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were built via the integration of compound–target networks and influenza virus–host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for the in silico identification of novel drug candidates from complex components of herbal medicine.

Multiple modes of action of myricetin in influenza A virus infection.

Influenza A virus remains a major threat to public health worldwide after its first pandemic. Scientists keep searching novel anti-influenza drugs, of which natural products present to be an important source. Myricetin, a natural flavonol compound, which exists in many edible plants, which has a wide range of biological activities, but its anti-influenza A virus activity is ambiguous. This study aims to evaluate the anti-influenza activity of myricetin and elucidate its underlying mechanism. Our results demonstrated that myricetin could significantly inhibit influenza A virus replication, reduce viral polymerase activity via selective inhibition of viral PB2 subunit, and the production of inflammatory cytokines by inhibiting TLR3 signaling pathway. The binding affinity analysis and the result of molecular docking revealed that myricetin interacted with the PB2 cap-binding pocket of influenza A virus. The above results suggested myricetin could exhibit anti-influenza virus activity with low cytotoxicity as well, and myricetin had low toxicity in BALB/c mice in vivo. Results from this study highlighted myricetin could be considered as a promising anti-influenza virus agent with dual inhibition profile. Furthermore, the compound with similar structure would provide a new option for the development of novel inhibitors against influenza A virus.

A Comparison of the Frequency of Prescription and Pharmacy Revisits between Baloxavir Marboxil and Neuraminidase Inhibitors in Influenza-Infected Pediatric Patients during the 2019–2020 Influenza Season

The novel anti-influenza virus agent baloxavir marboxil is a selective inhibitor of an influenza cap-dependent endonuclease. Although a single oral dose in tablet form of baloxavir marboxil is expected to improve drug compliance and rapidly reduce viral titers for pediatric patients with influenza, there is a concern that baloxavir marboxil-resistant influenza A variants could be generated. In this study, we investigated the frequency of prescription and pharmacy revisits for baloxavir marboxil at an outpatient clinic compared with that of neuraminidase inhibitors in pediatric patients with influenza. A total of 475 pediatric patients who were infected with the influenza virus visited the pharmacy between December 2019 and March 2020. Baloxavir marboxil (n = 149), oseltamivir (n = 161) and laninamivir (n = 162) were mainly prescribed and only a few patients were treated with peramivir (n = 2) or zanamivir (n = 1). Baloxavir marboxil-, oseltamivir- and laninamivir-treated pediatric patients were enrolled, and a log-rank test showed that the revisits of pediatric patients who were taking baloxavir marboxil was lower than those for oseltamivir (p < 0.001). Moreover, Cox proportional hazards models also revealed that baloxavir marboxil decreased the risk of revisits in comparison to oseltamivir (hazard ratio 0.28, 95% confidence interval 0.11-0.70, p = 0.006), while no difference was found between laninamivir and baloxavir marboxil. Although there is a need to acquire appropriate and relevant information concerning resistant viruses, our results suggest that baloxavir marboxil may be a useful drug for treating pediatric patients with influenza infections.

Efficacy of baloxavir marboxil on household transmission of influenza infection

BackgroundBaloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir.MethodsBetween October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses.ResultsIn total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11–57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6–15.6) in the baloxavir group and 13.5% (95% CI: 9.8–17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0–6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33–5.82, p < 0.01) and not being on baloxavir treatment. (OR: 0.63, 95% CI: 0.30–1.32, p = 0.22).ConclusionThe household secondary attack rate of influenza was comparable in patients treated with baloxavir vs oseltamivir. Therefore, baloxavir can be used as an alternative therapy to oseltamivir in reducing household transmission of influenza.Trial registrationPatients in this study were retrospectively registered. https://www.tosei.or.jp/clinical/pdf/2_influenza.pdf.

Anti-Influenza A Virus Activity of Rhamnan Sulfate from Green Algae Monostroma nitidum in Mice with Normal and Compromised Immunity.

Influenza viruses cause a significant public health burden each year despite the availability of anti-influenza drugs and vaccines. Therefore, new anti-influenza virus agents are needed. Rhamnan sulfate (RS) is a sulfated polysaccharide derived from the green alga Monostroma nitidum. Here, we aimed to demonstrate the antiviral activity of RS, especially against influenza A virus (IFV) infection, in vitro and in vivo. RS showed inhibitory effects on viral proliferation of enveloped viruses in vitro. Evaluation of the anti-IFV activity of RS in vitro showed that it inhibited both virus adsorption and entry steps. The oral administration of RS in IFV-infected immunocompetent and immunocompromised mice suppressed viral proliferation in both mouse types. The oral administration of RS also had stimulatory effects on neutralizing antibody production. Fluorescent analysis showed that RS colocalized with M cells in Peyer’s patches, suggesting that RS bound to the M cells and may be incorporated into the Peyer’s patches, which are essential to intestinal immunity. In summary, RS inhibits influenza virus infection and promotes antibody production, suggesting that RS is a potential candidate for the treatment of influenza virus infections.

Insights into RNA-dependent RNA Polymerase Inhibitors as Antiinfluenza Virus Agents.

Influenza is a seasonal disease that affects millions of people every year and has a significant economic impact. Vaccines are the best strategy to fight this viral pathology, but they are not always available or administrable, prompting the search for antiviral drugs. RNA-dependent RNA polymerase (RdRp) recently emerged as a promising target because of its key role in viral replication and its high conservation among viral strains. This review presents an overview of the most interesting RdRp inhibitors that have been discussed in the literature since 2000. Compounds already approved or in clinical trials and a selection of inhibitors endowed with different scaffolds are described, along with the main features responsible for their activity. RdRp inhibitors are emerging as a new strategy to fight viral infections and the importance of this class of drugs has been confirmed by the FDA approval of baloxavir marboxil in 2018. Despite the complexity of the RdRp machine makes the identification of new compounds a challenging research topic, it is likely that in the coming years, this field will attract the interest of a number of academic and industrial scientists because of the potential strength of this therapeutic approach.

Evolution and Biological Evaluation of Matrinic Derivatives with Amantadine Fragments As New Anti-Influenza Virus Agents.

A series of novel tricyclic matrinic derivatives with 11-adamantyl substitution were designed, synthesized, and evaluated for their activities against Influenza A H3N2 virus, based on the privileged structure strategy. Structure-activity relationship (SAR) analysis indicated that the introduction of an 11-adamantyl might be helpful for the potency. Among them, compounds 9f and 9j exhibited the promising anti-H3N2 activities with IC50 values of 7.2 μM and 10.2 μM, respectively, better than that of lead 1. Their activities were further confirmed at the protein level. Moreover, compound 9f displayed a high pharmacokinetic (PK) stability profile in whole blood and a safety profile in vivo. In primary mechanism, compound 9f could inhibit the virus replication cycle at early stage by targeting M2 protein, consistent with that of the parent amantadine. This study provided powerful information for further strategic optimization to develop these compounds into a new class of anti-influenza agents.

Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble β-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of β-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached β-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated β-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Six series of semisynthetic lipophilic glycopeptide antibiotic derivatives were evaluated for in vitro activity against influenza A and B viruses. The new teicoplanin pseudoaglycon-derived lipoglycopeptides were prepared by coupling one or two side chains to the N-terminus of the glycopeptide core, using various conjugation methods. Three series of derivatives bearing two lipophilic groups were synthesized by attaching bis-alkylthio maleimides directly or through linkers of different lengths to the glycopeptide. Access to the fourth and fifth series of compounds was achieved by click chemistry, introducing single alkyl/aryl chains directly or through a tetraethylene glycol linker to the same position. A sixth group of semisynthetic derivatives was obtained by sulfonylation of the N-terminus. Of the 42 lipophilic teicoplanin pseudoaglycon derivatives tested, about half showed broad activity against influenza A and B viruses, with some of them having reasonable or no cytotoxicity. Minor differences in the side chain length as well as lipophilicity appeared to have significant impact on antiviral activity and cytotoxicity. Several lipoglycopeptides were also found to be active against human coronavirus.

Design, synthesis and biological evaluation of water-soluble per-O-methylated cyclodextrin-C60 conjugates as anti-influenza virus agents

The most common fullerene member C60 displays many biological applications, such as, anticancer, human immunodeficiency virus and hepatitis C virus inhibitors, O2 uptake inhibitor and vectors for drug and DNA. Nevertheless, the innate hydrophobicity of C60 constrains its further development. We introduced cyclodextrins to enhance the water-solubility of C60. Nine cyclodextrin-C60 conjugates, including seven α-cyclodextrin-C60 conjugates and two γ-cyclodextrin-C60 conjugates, were designed and synthesized. All of these conjugates did not show obvious cytotoxicity. The anti-influenza virus activity of nine conjugates was assessed. Two γ-cyclodextrin-C60 conjugates, which were relatively more water-soluble, exerted higher inhibition with IC50 values of 87.73 μM and 75.06 μM, respectively, than seven α-cyclodextrin-C60 conjugates.