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Peptide inhibitors against influenza virus

Rajik M, Yusoff K

Antivir Chem Chemother, 2011;21(4):151-4.
PMID: 21602612 DOI: 10.3851/IMP1728

Influenza A virus is a particularly problematic virus because of its ability to cause high levels of morbidity on a global scale within a remarkably short period of time. It also has the potential to kill very large numbers of people as occurred in the Spanish influenza pandemic in 1918. Options for antiviral therapy are limited because of the paucity of available drugs and the rapid mutation rate of the virus leading to the emergence of drug-resistant strains. The current H1N1 pandemic and potential threats posed by other strains highlight the need to develop novel therapeutic and prophylactic strategies. Here, we summarize the current state and recent developments of peptide-based inhibitors of influenza A virus.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects
Novel Piperine compound AB05 (N-5-(3,4-dimethoxyphenyl) -2E,4E pentadienylpiperidine) inhibits H1N1 influenza virus propagation in vitro

Mohammed A, Velu AB, Al-Hakami AM, Meenakshisundaram B, Esther P, Abdelwahid SA, et al.

Trop Biomed, 2020 Dec 01;37(4):1062-1073.
PMID: 33612758 DOI: 10.47665/tb.37.4.1062

Pandemic H1N1 influenza virus respiratory illness has become an inevitable global health concern. With antigenic drift, it becomes necessary to have drugs over tailor-made HIN1 vaccine every year. In the current study, we screened many Piperine derivative in which, N-5-(3,4-dimethoxyphenyl)-2E,4E-pentadienylpiperidine (AB05) and was further studied for anti-H1N1influenza virus activity and compared with other stains in-vitro on MDCK cell line. Initial cytotoxic doses of AB05 for the MDCK cell line were > 25µM. The results showed a dose-dependent reduction of the viral plaque's in the adsorption assay with EC50 of 0.33 µM. The mechanism of AB05 was by inhibition of matured viral release as evaluated by the time of virus addition with incubation of 6-10 hours. With the promising H1N1 virucidal activity of AB05, we included various strains of human influenza virus to screen AB05 inhibition of Neuraminidase (NA). The result showed 70% NA inhibition in WSN (H1N1), 90% in H3N2 and Influenza B and 49% in Tamiflu resistant H1N1). Further our In silco docking studies substantiated experimental results by showing the difference in binding and cooperation between H1N1 and N3N2. Together these observations illustrate that Piperine derivative AB05 is a promising lead molecule which needs further evaluation in animal models.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects*
Anti-influenza virus activity of tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone

Yazawa K, Kurokawa M, Obuchi M, Li Y, Yamada R, Sadanari H, et al.

Antivir Chem Chemother, 2011;22(1):1-11.
PMID: 21860068 DOI: 10.3851/IMP1782

We examined the anti-influenza virus activity of tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone, against five viruses: A/Solomon islands/3/2006 (H1N1), A/Hiroshima/52/2005 (H3N2), A/California/07/2009 (H1N1pdm), A/Narita/1/2009 (H1N1pdm) and B/Malaysia/2506/2004 strains in vitro and against A/PR/8/34 virus in vivo.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects
Fulltext Edible bird's nest modulate intracellular molecular pathways of influenza A virus infected cells

Haghani A, Mehrbod P, Safi N, Kadir FA, Omar AR, Ideris A

BMC Complement Altern Med, 2017 Jan 05;17(1):22.
PMID: 28056926 DOI: 10.1186/s12906-016-1498-x

BACKGROUND: Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized.
METHODS: In this study, EBNs that underwent different enzymatic preparation were tested against IAV infected cells. 50% cytotoxic concentration (CC50) and 50% inhibitory concentration (IC50) of the EBNs against IAV strain A/Puerto Rico/8/1934(H1N1) were determined by HA and MTT assays. Subsequently, the sialic acid content of the used EBNs were analyzed by fluorometric HPLC. Western Blotting and immunofluorescent staining were used to investigate the effects of EBNs on early endosomal trafficking and autophagy process of influenza virus.
RESULTS: This study showed that post inoculations of EBNs after enzymatic preparations have the highest efficacy to inhibit IAV. While CC50 of the tested EBNs ranged from 27.5-32 mg/ml, the IC50 of these compounds ranged between 2.5-4.9 mg/ml. EBNs could inhibit IAV as efficient as commercial antiviral agents, such as amantadine and oseltamivir with different mechanisms of action against IAV. The antiviral activity of these EBNs correlated with the content of N-acetyl neuraminic acid. EBNs could affect early endosomal trafficking of the virus by reducing Rab5 and RhoA GTPase proteins and also reoriented actin cytoskeleton of IAV infected cells. In addition, for the first time this study showed that EBNs can inhibit intracellular autophagy process of IAV life cycle as evidenced by reduction of LC3-II and increasing of lysosomal degradation.
CONCLUSIONS: The results procured in this study support the potential of EBNs as supplementary medication or alternative to antiviral agents to inhibit influenza infections. Evidently, EBNs can be a promising antiviral agent; however, these natural compounds should be screened for their metabolites prior to usage as therapeutic approach.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects*
Structurally conserved binding sites of hemagglutinin as targets for influenza drug and vaccine development

Yusuf M, Konc J, Sy Bing C, Trykowska Konc J, Ahmad Khairudin NB, Janezic D, et al.

J Chem Inf Model, 2013 Sep 23;53(9):2423-36.
PMID: 23980878 DOI: 10.1021/ci400421e

ProBiS is a new method to identify the binding site of protein through local structural alignment against the nonredundant Protein Data Bank (PDB), which may result in unique findings compared to the energy-based, geometry-based, and sequence-based predictors. In this work, binding sites of Hemagglutinin (HA), which is an important target for drugs and vaccines in influenza treatment, have been revisited by ProBiS. For the first time, the identification of conserved binding sites by local structural alignment across all subtypes and strains of HA available in PDB is presented. ProBiS finds three distinctive conserved sites on HA's structure (named Site 1, Site 2, and Site 3). Compared to other predictors, ProBiS is the only one that accurately defines the receptor binding site (Site 1). Apart from that, Site 2, which is located slightly above the TBHQ binding site, is proposed as a potential novel conserved target for membrane fusion inhibitor. Lastly, Site 3, located around Helix A at the stem domain and recently targeted by cross-reactive antibodies, is predicted to be conserved in the latest H7N9 China 2013 strain as well. The further exploration of these three sites provides valuable insight in optimizing the influenza drug and vaccine development.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects
Fulltext Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

Hariono M, Abdullah N, Damodaran KV, Kamarulzaman EE, Mohamed N, Hassan SS, et al.

Sci Rep, 2016 12 20;6:38692.
PMID: 27995961 DOI: 10.1038/srep38692

We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects
Fulltext Simvastatin modulates cellular components in influenza A virus-infected cells

Mehrbod P, Hair-Bejo M, Tengku Ibrahim TA, Omar AR, El Zowalaty M, Ajdari Z, et al.

Int J Mol Med, 2014 Jul;34(1):61-73.
PMID: 24788303 DOI: 10.3892/ijmm.2014.1761

Influenza A virus is one of the most important health risks that lead to significant respiratory infections. Continuous antigenic changes and lack of promising vaccines are the reasons for the unsuccessful treatment of influenza. Statins are pleiotropic drugs that have recently served as anti-influenza agents due to their anti-inflammatory activity. In this study, the effect of simvastatin on influenza A-infected cells was investigated. Based on the MTT cytotoxicity test, hemagglutination (HA) assay and qPCR it was found that simvastatin maintained cell viability and decreased the viral load significantly as compared to virus-inoculated cells. The expression of important pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6 and interferon-γ), which was quantified using ELISA showed that simvastatin decreased the expression of pro-inflammatory cytokines to an average of 2-fold. Furthermore, the modulation of actin filament polymerization was determined using rhodamine staining. Endocytosis and autophagy processes were examined by detecting Rab and RhoA GTPase protein prenylation and LC3 lipidation using western blotting. The results showed that inhibiting GTPase and LC3 membrane localization using simvastatin inhibits influenza replication. Findings of this study provide evidence that modulation of RhoA, Rabs and LC3 may be the underlying mechanisms for the inhibitory effects of simvastatin as an anti-influenza compound.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects*
Anti-infective activities of 11 plants species used in traditional medicine in Malaysia

Nor Azman NS, Hossan MS, Nissapatorn V, Uthaipibull C, Prommana P, Jin KT, et al.

Exp Parasitol, 2018 Nov;194:67-78.
PMID: 30268422 DOI: 10.1016/j.exppara.2018.09.020

Treatment of drug resistant protozoa, bacteria, and viruses requires new drugs with alternative chemotypes. Such compounds could be found from Southeast Asian medicinal plants. The present study examines the cytotoxic, antileishmanial, and antiplasmodial effects of 11 ethnopharmacologically important plant species in Malaysia. Chloroform extracts were tested for their toxicity against MRC-5 cells and Leishmania donovani by MTT, and chloroquine-resistant Plasmodium falciparum K1 strain by Histidine-Rich Protein II ELISA assays. None of the extract tested was cytotoxic to MRC-5 cells. Extracts of Uvaria grandiflora, Chilocarpus costatus, Tabernaemontana peduncularis, and Leuconotis eugenifolius had good activities against L. donovani with IC50 influenza virus (IC50 = 30.4 ± 11 μg/mL) and was active against Coxsackie virus B3 (IC50 = 7.1 ± 3.0 μg/mL). β-Amyrin from L. eugenifolius inhibited L. donovani with IC50 value of 15.4 ± 0.01 μM. Furanodienone from C. aeruginosa inhibited L. donovani and P. falciparum K1 with IC50 value of 39.5 ± 0.2 and 17.0 ± 0.05 μM, respectively. Furanodienone also inhibited the replication of influenza and Coxsackie virus B3 with IC50 value of 4.0 ± 0.5 and 7.2 ± 1.4 μg/mL (Ribavirin: IC50: 15.6 ± 2.0 μg/mL), respectively. Our study provides evidence that medicinal plants in Malaysia have potentials as a source of chemotypes for the development of anti-infective leads.

Matched MeSH terms: Influenza A Virus, H1N1 Subtype/drug effects