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10 pages, 3634 KiB

Open AccessCommunication

In Vitro and in Vivo Antiviral Activity of Mizoribine Against Foot-And-Mouth Disease Virus

by Shi-Fang Li, Mei-Jiao Gong, Yue-Feng Sun, Jun-Jun Shao, Yong-Guang Zhang and Hui-Yun Chang

Molecules 2019, 24(9), 1723; https://doi.org/10.3390/molecules24091723 - 3 May 2019

Cited by 13 | Viewed by 3840

Abstract

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4–7 days post-vaccination, the only alternative method to control the spread of [...] Read more.

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4–7 days post-vaccination, the only alternative method to control the spread of FMD virus (FMDV) during outbreaks is the application of antiviral agents. Hence, it is important to identify effective antiviral agents against FMDV infection. In this study, we found that mizoribine has potent antiviral activity against FMDV replication in IBRS-2 cells. A time-of-drug-addition assay demonstrated that mizoribine functions at the early stage of replication. Moreover, mizoribine also showed antiviral effect on FMDV in vivo. In summary, these results revealed that mizoribine could be a potential antiviral drug against FMDV. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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30 pages, 11460 KiB

Open AccessArticle

Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

by Megan E. Meuser, Adel A. Rashad, Gabriel Ozorowski, Alexej Dick, Andrew B. Ward and Simon Cocklin

Molecules 2019, 24(8), 1581; https://doi.org/10.3390/molecules24081581 - 22 Apr 2019

Cited by 8 | Viewed by 4540

Abstract

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published [...] Read more.

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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13 pages, 4875 KiB

Open AccessArticle

Chenodeoxycholic Acid from Bile Inhibits Influenza A Virus Replication via Blocking Nuclear Export of Viral Ribonucleoprotein Complexes

by Ling Luo, Weili Han, Jinyan Du, Xia Yang, Mubing Duan, Chenggang Xu, Zhenling Zeng, Weisan Chen and Jianxin Chen

Molecules 2018, 23(12), 3315; https://doi.org/10.3390/molecules23123315 - 14 Dec 2018

Cited by 23 | Viewed by 3871

Abstract

Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous [...] Read more.

Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous small molecules from host, such as estradiol and omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protection D1 (PD1), were demonstrated to be capable of inhibiting IAV infection. Chenodeoxycholic acid (CDCA), one of the main primary bile acids, is synthesized from cholesterol in the liver and classically functions in emulsification and absorption of dietary fats. Clinically, CDCA has been used in the treatment of patients with cholesterol gallstones for more than five decades. In this study, we showed that CDCA attenuated the replication of three subtypes of influenza A virus, including a highly pathogenic H5N1 strain, in A549 and MDCK cell cultures with IC₅₀ ranging from 5.5 to 11.5 μM. Mechanistically, CDCA effectively restrained the nuclear export of viral ribonucleoprotein (vRNP) complexes. In conclusion, as an endogenous physiological small molecule, CDCA can inhibit IAV replication in vitro, at least in part, by blocking vRNP nuclear export, and affords further studies for development as a potential antiviral agent against IAV infections. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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15 pages, 3521 KiB

Open AccessArticle

Alteration of Intestinal Flora Stimulates Pulmonary microRNAs to Interfere with Host Antiviral Immunity in Influenza

by Peng Pang, Bin Yu, Yucong Shi, Li Deng, Huachong Xu, Sizhi Wu and Xiaoyin Chen

Molecules 2018, 23(12), 3151; https://doi.org/10.3390/molecules23123151 - 30 Nov 2018

Cited by 16 | Viewed by 4576

Abstract

The intestinal flora may be an important and modifiable factor that contributes to the immune response in influenza. To investigate the effect of intestinal flora alteration induced by antibiotic interference on microRNA (miRNA) communication in antiviral immunity, BALB/c mice received two weeks of [...] Read more.

The intestinal flora may be an important and modifiable factor that contributes to the immune response in influenza. To investigate the effect of intestinal flora alteration induced by antibiotic interference on microRNA (miRNA) communication in antiviral immunity, BALB/c mice received two weeks of antibiotic treatment before infection with the influenza A virus. The changes in intestinal flora and pulmonary flora were detected and analyzed by 16S ribosomal RNA (rRNA) gene sequencing. The amplification of the influenza virus in the lungs was measured by RT-PCR. The involvement of pulmonary miRNA was explored using miRNA microarray analysis. The results showed that the antibiotics destroyed the symbiotic relationship of the intestinal flora, resulting in a reduction in bacterial diversity, but they did not affect the pulmonary flora. The alteration of intestinal flora affected the expression of pulmonary miRNAs and resulted in an enhancement of pulmonary influenza virus amplification. The conclusion is that alteration of intestinal flora induced by antibiotic interference affected the expression of pulmonary miRNAs to interfere with host antiviral immunity, of which miR-146b and miR-29c might be good resources of resistance to influenza under antibiotic abuse. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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13 pages, 1013 KiB

Open AccessArticle

A Computational Approach for the Prediction of HIV Resistance Based on Amino Acid and Nucleotide Descriptors

by Olga Tarasova, Nadezhda Biziukova, Dmitry Filimonov and Vladimir Poroikov

Molecules 2018, 23(11), 2751; https://doi.org/10.3390/molecules23112751 - 24 Oct 2018

Cited by 23 | Viewed by 3630

Abstract

The high variability of the human immunodeficiency virus (HIV) is an important cause of HIV resistance to reverse transcriptase and protease inhibitors. There are many variants of HIV type 1 (HIV-1) that can be used to model sequence-resistance relationships. Machine learning methods are [...] Read more.

The high variability of the human immunodeficiency virus (HIV) is an important cause of HIV resistance to reverse transcriptase and protease inhibitors. There are many variants of HIV type 1 (HIV-1) that can be used to model sequence-resistance relationships. Machine learning methods are widely and successfully used in new drug discovery. An emerging body of data regarding the interactions of small drug-like molecules with their protein targets provides the possibility of building models on “structure-property” relationships and analyzing the performance of various machine-learning techniques. In our research, we analyze several different types of descriptors in order to predict the resistance of HIV reverse transcriptase and protease to the marketed antiretroviral drugs using the Random Forest approach. First, we represented amino acid sequences as a set of short peptide fragments, which included several amino acid residues. Second, we represented nucleotide sequences as a set of fragments, which included several nucleotides. We compared these two approaches using open data from the Stanford HIV Drug Resistance Database. We have determined the factors that modulate the performance of prediction: in particular, we observed that the prediction performance was more sensitive to certain drugs than a type of the descriptor used. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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16 pages, 8860 KiB

Open AccessArticle

Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy

by Yan-Xiang Wang, Lu Yang, Hui-Qiang Wang, Xiao-Qiang Zhao, Ting Liu, Ying-Hong Li, Qing-Xuan Zeng, Yu-Huan Li and Dan-Qing Song

Molecules 2018, 23(8), 2084; https://doi.org/10.3390/molecules23082084 - 20 Aug 2018

Cited by 25 | Viewed by 5640

Abstract

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent [...] Read more.

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC₅₀ values of 7.12–14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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15 pages, 1992 KiB

Open AccessArticle

HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence

by Xue Zhi Zhao, Mathieu Métifiot, Evgeny Kiselev, Jacques J. Kessl, Kasthuraiah Maddali, Christophe Marchand, Mamuka Kvaratskhelia, Yves Pommier and Terrence R. Burke, Jr.

Molecules 2018, 23(8), 1858; https://doi.org/10.3390/molecules23081858 - 26 Jul 2018

Cited by 4 | Viewed by 4142

Abstract

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity [...] Read more.

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69–75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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Review

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24 pages, 8658 KiB

Open AccessReview

Carbazole Derivatives as Antiviral Agents: An Overview

by Anna Caruso, Jessica Ceramella, Domenico Iacopetta, Carmela Saturnino, Maria Vittoria Mauro, Rosalinda Bruno, Stefano Aquaro and Maria Stefania Sinicropi

Molecules 2019, 24(10), 1912; https://doi.org/10.3390/molecules24101912 - 17 May 2019

Cited by 97 | Viewed by 8016

Abstract

Viruses represent the most common cause of infectious diseases worldwide and those with rapid propagation and high infection rates cause human and animal pandemics. These fast-spreading diseases are generally treated with antiviral drugs but, often, drug resistance occurs because of the ability of [...] Read more.

Viruses represent the most common cause of infectious diseases worldwide and those with rapid propagation and high infection rates cause human and animal pandemics. These fast-spreading diseases are generally treated with antiviral drugs but, often, drug resistance occurs because of the ability of the pathogens to mutate rapidly and become less susceptible to the treatments. Even though new antivirals have been approved, e.g., in HIV (human immunodeficiency virus) and HCV (hepatitis C virus) therapeutic areas, the need to dispose of new pharmaceutical tools for the management of infections that still have no treatment is of growing interest. In these areas, carbazole represents an important privileged scaffold in drug discovery. Many compounds with a carbazolic core have been developed and some of them have shown antiviral activity. This review provides an overview on some already known carbazole derivatives, pointing the attention on the running progresses in identifying new molecules with carbazolic structure, that have shown interesting and encouraging in vitro and in vivo properties. These drugs may be exploited as valid alternatives in antiviral therapy. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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12 pages, 2644 KiB

Open AccessReview

Hotoda’s Sequence and Anti-HIV Activity: Where Are We Now?

by Valeria Romanucci, Armando Zarrelli and Giovanni Di Fabio

Molecules 2019, 24(7), 1417; https://doi.org/10.3390/molecules24071417 - 10 Apr 2019

Cited by 8 | Viewed by 3044

Abstract

The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. [...] Read more.

The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. In this review, we have reported the history of a strong anti-HIV agent: the 6-mer d(TGGGAG) sequence, commonly called “Hotoda’s sequence”. In particular, all findings reported on this sequence and its modified sequences have been discussed considering the following research phases: (i) discovery of the first 5′-modified active d(TGGGAG) sequences; (ii) synthesis of a variety of end-modified d(TGGGAG) sequences; (iii) biophysical and NMR investigations of natural and modified Hotoda’s sequences; (iv); kinetic studies on the most active 5′-modified d(TGGGAG) sequences; and (v) extensive anti-HIV screening of G-quadruplexes formed by d(TGGGAG) sequences. This review aims to clarify all results obtained over the years on Hotoda’s sequence, revealing its potentiality as a strong anti-HIV agent (EC₅₀ = 14 nM). Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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28 pages, 680 KiB

Open AccessReview

CRISPR/Cas9-Based Antiviral Strategy: Current Status and the Potential Challenge

by Choongho Lee

Molecules 2019, 24(7), 1349; https://doi.org/10.3390/molecules24071349 - 5 Apr 2019

Cited by 46 | Viewed by 7827

Abstract

From its unexpected discovery as a bacterial adaptive immune system to its countless applications as one of the most versatile gene-editing tools, the CRISPR/Cas9 system has revolutionized every field of life science. Virology is no exception to this ever-growing list of CRISPR/Cas9-based applications. [...] Read more.

From its unexpected discovery as a bacterial adaptive immune system to its countless applications as one of the most versatile gene-editing tools, the CRISPR/Cas9 system has revolutionized every field of life science. Virology is no exception to this ever-growing list of CRISPR/Cas9-based applications. Direct manipulation of a virus genome by CRISPR/Cas9 has enabled a systematic study of cis-elements and trans-elements encoded in a virus genome. In addition, this virus genome-specific mutagenesis by CRISPR/Cas9 was further funneled into the development of a novel class of antiviral therapy targeting many incurable chronic viral infections. In this review, a general concept on the CRISPR/Cas9-based antiviral strategy will be described first. To understand the current status of the CRISPR/Cas9-based antiviral approach, a series of recently published antiviral studies involving CRISPR/Cas9-mediated control of several clinically-relevant viruses including human immunodeficiency virus, hepatitis B virus, herpesviruses, human papillomavirus, and other viruses will be presented. Lastly, the potential challenge and future prospect for successful clinical translation of this CRISPR/Cas9-based antiviral method will be discussed. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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20 pages, 995 KiB

Open AccessReview

Novel Therapeutics for Epstein–Barr Virus

by Graciela Andrei, Erika Trompet and Robert Snoeck

Molecules 2019, 24(5), 997; https://doi.org/10.3390/molecules24050997 - 12 Mar 2019

Cited by 84 | Viewed by 20157

Abstract

Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later [...] Read more.

Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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11 pages, 3859 KiB

Open AccessReview

CCR5/CXCR4 Dual Antagonism for the Improvement of HIV Infection Therapy

by Fedora Grande, Maria Antonietta Occhiuzzi, Bruno Rizzuti, Giuseppina Ioele, Michele De Luca, Paola Tucci, Valentina Svicher, Stefano Aquaro and Antonio Garofalo

Molecules 2019, 24(3), 550; https://doi.org/10.3390/molecules24030550 - 2 Feb 2019

Cited by 25 | Viewed by 12340

Abstract

HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor [...] Read more.

HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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Other

Jump to: Research, Review

7 pages, 616 KiB

Open AccessBrief Report

Combining New Non-Nucleoside Reverse Transcriptase Inhibitors (RTIs) with AZT Results in Strong Synergism against Multi-RTI-Resistant HIV-1 Strains

by Fei Yu, Wen Li, Lili Wang, Yu Dai, Xin Lu, Qian Wang, Lan Xie and Shibo Jiang

Molecules 2018, 23(7), 1599; https://doi.org/10.3390/molecules23071599 - 2 Jul 2018

Cited by 3 | Viewed by 3973

Abstract

Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, [...] Read more.

Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, we demonstrated that combining azidothymidine (AZT) with a new NNRTIs under development, diarylpyridine (DAPA)-2e, diarylanilin (DAAN)-14h, or DAAN-15h, resulted in strong synergism against infection by divergent HIV-1 strains, including those resistant to NRTIs and NNRTIs, suggesting the potential for developing these novel NNRTIs as salvage therapy for HIV/acquired immune deficiency syndrome (AIDS) patients. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)

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