International Journal of Molecular Sciences

Research

Jump to: Review

13 pages, 2030 KiB

Open AccessArticle

by Bryan Saldivar-Espinoza, Pol Garcia-Segura, Nil Novau-Ferré, Guillem Macip, Ruben Martínez, Pere Puigbò, Adrià Cereto-Massagué, Gerard Pujadas and Santiago Garcia-Vallve

Int. J. Mol. Sci. 2023, 24(10), 9072; https://doi.org/10.3390/ijms24109072 - 22 May 2023

Cited by 8 | Viewed by 2135

Abstract

Mutation research is crucial for detecting and treating SARS-CoV-2 and developing vaccines. Using over 5,300,000 sequences from SARS-CoV-2 genomes and custom Python programs, we analyzed the mutational landscape of SARS-CoV-2. Although almost every nucleotide in the SARS-CoV-2 genome has mutated at some time, [...] Read more.

Mutation research is crucial for detecting and treating SARS-CoV-2 and developing vaccines. Using over 5,300,000 sequences from SARS-CoV-2 genomes and custom Python programs, we analyzed the mutational landscape of SARS-CoV-2. Although almost every nucleotide in the SARS-CoV-2 genome has mutated at some time, the substantial differences in the frequency and regularity of mutations warrant further examination. C>U mutations are the most common. They are found in the largest number of variants, pangolin lineages, and countries, which indicates that they are a driving force behind the evolution of SARS-CoV-2. Not all SARS-CoV-2 genes have mutated in the same way. Fewer non-synonymous single nucleotide variations are found in genes that encode proteins with a critical role in virus replication than in genes with ancillary roles. Some genes, such as spike (S) and nucleocapsid (N), show more non-synonymous mutations than others. Although the prevalence of mutations in the target regions of COVID-19 diagnostic RT-qPCR tests is generally low, in some cases, such as for some primers that bind to the N gene, it is significant. Therefore, ongoing monitoring of SARS-CoV-2 mutations is crucial. The SARS-CoV-2 Mutation Portal provides access to a database of SARS-CoV-2 mutations. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

11 pages, 881 KiB

Open AccessArticle

Drug Potency Prediction of SARS-CoV-2 Main Protease Inhibitors Based on a Graph Generative Model

by Sarah Fadlallah, Carme Julià, Santiago García-Vallvé, Gerard Pujadas and Francesc Serratosa

Int. J. Mol. Sci. 2023, 24(10), 8779; https://doi.org/10.3390/ijms24108779 - 15 May 2023

Viewed by 1279

Abstract

The prediction of a ligand potency to inhibit SARS-CoV-2 main protease (M-pro) would be a highly helpful addition to a virtual screening process. The most potent compounds might then be the focus of further efforts to experimentally validate their potency and improve them. [...] Read more.

The prediction of a ligand potency to inhibit SARS-CoV-2 main protease (M-pro) would be a highly helpful addition to a virtual screening process. The most potent compounds might then be the focus of further efforts to experimentally validate their potency and improve them. A computational method to predict drug potency, which is based on three main steps, is defined: (1) defining the drug and protein in only one 3D structure; (2) applying graph autoencoder techniques with the aim of generating a latent vector; and (3) using a classical fitting model to the latent vector to predict the potency of the drug. Experiments in a database of 160 drug-M-pro pairs, from which the

{p I C}_{50}

is known, show the ability of our method to predict their drug potency with high accuracy. Moreover, the time spent to compute the

{p I C}_{50}

of the whole database is only some seconds, using a current personal computer. Thus, it can be concluded that a computational tool that predicts, with high reliability, the

{p I C}_{50}

in a cheap and fast way is achieved. This tool, which can be used to prioritize which virtual screening hits, will be further examined in vitro. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

13 pages, 3079 KiB

Open AccessArticle

Identification of Molecular Mechanisms Involved in Viral Infection Progression Based on Text Mining: Case Study for HIV Infection

by Olga Tarasova, Nadezhda Biziukova, Andrey Shemshura, Dmitry Filimonov, Dmitry Kireev, Anastasia Pokrovskaya and Vladimir V. Poroikov

Int. J. Mol. Sci. 2023, 24(2), 1465; https://doi.org/10.3390/ijms24021465 - 11 Jan 2023

Cited by 3 | Viewed by 1654

Abstract

Viruses cause various infections that may affect human lifestyle for durations ranging from several days to for many years. Although preventative and therapeutic remedies are available for many viruses, they may still have a profound impact on human life. The human immunodeficiency virus [...] Read more.

Viruses cause various infections that may affect human lifestyle for durations ranging from several days to for many years. Although preventative and therapeutic remedies are available for many viruses, they may still have a profound impact on human life. The human immunodeficiency virus type 1 is the most common cause of HIV infection, which represents one of the most dangerous and complex diseases since it affects the immune system and causes its disruption, leading to secondary complications and negatively influencing health-related quality of life. While highly active antiretroviral therapy may decrease the viral load and the velocity of HIV infection progression, some individual peculiarities may affect viral load control or the progression of T-cell malfunction induced by HIV. Our study is aimed at the text-based identification of molecular mechanisms that may be involved in viral infection progression, using HIV as a case study. Specifically, we identified human proteins and genes which commonly occurred, overexpressed or underexpressed, in the collections of publications relevant to (i) HIV infection progression and (ii) acute and chronic stages of HIV infection. Then, we considered biological processes that are controlled by the identified protein and genes. We verified the impact of the identified molecules in the associated clinical study. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

19 pages, 4249 KiB

Open AccessArticle

Alloferon and Zanamivir Show Effective Antiviral Activity against Influenza A Virus (H1N1) Infection In Vitro and In Vivo

by Dahae Lee, Hyejung Jo, Yoojin Jang, Suhyun Bae, Tomoyo Agura, Dongmin Kang, Minsoo Kang, Yuri Kim, Nam-Hyuk Cho, Yejin Kim and Jae Seung Kang

Int. J. Mol. Sci. 2023, 24(1), 678; https://doi.org/10.3390/ijms24010678 - 30 Dec 2022

Cited by 4 | Viewed by 2676

Abstract

The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza [...] Read more.

The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza A/H1N1 in 2009. However, the emergence of drug-resistant strains can occur rapidly. Alloferon, an immunomodulatory drug developed as an NK cell activator, exerts antiviral effects against various viruses, particularly influenza viruses. Therefore, alloferon and zanamivir were administered in combination in an effort to improve the antiviral effect of zanamivir by reducing H1N1 resistance. First, we confirmed that administration of combined treatment would result in effective inhibition of viral proliferation in MDCK and A549 cells infected with H1N1. Production of IL-6 and MIP-1α in these cells and the activity of p38 MAPK and c-Jun that are increased by H1N1 were inhibited by combined treatment. Mice were then infected intranasally with H1N1, and examination of the antiviral efficacy of the alloferon/zanamivir combination was performed. The results showed that combined treatment after infection with H1N1 prevented weight loss, increased the survival rate, and improved lung fibrosis. Combined treatment also resulted in reduced infiltration of neutrophils and macrophages into the lungs. Combined treatment effectively inhibited the activity of p38 MAPK and c-Jun in lung tissue, which was increased by infection with H1N1. Therefore, the combination of alloferon/zanamivir effectively prevents the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and migration of inflammatory cells into lung tissue. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

15 pages, 2438 KiB

Open AccessArticle

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle

by Milene D. Miranda, Otávio Augusto Chaves, Alice S. Rosa, Alexandre R. Azevedo, Luiz Carlos da Silva Pinheiro, Vinicius C. Soares, Suelen S. G. Dias, Juliana L. Abrantes, Alice Maria R. Bernardino, Izabel C. P. Paixão, Thiago Moreno L. Souza and Carlos Frederico L. Fontes

Int. J. Mol. Sci. 2022, 23(15), 8135; https://doi.org/10.3390/ijms23158135 - 23 Jul 2022

Cited by 2 | Viewed by 2112

Abstract

Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on [...] Read more.

Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration (EC₅₀) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 ± 0.10, 1.00 ± 0.05, and 0.70 ± 0.10 µM, respectively. These compounds presented high 50% cytotoxic concentration (CC₅₀) values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules would impair, we performed adsorption and penetration inhibition assays and time-of-addition experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57 interfered with the virus replication during its α- and γ-phases and decreased ICP27 content during initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a strong decrease in viral gD content, which was reinforced by in silico calculations that suggested AM-57 interacts preferentially with the viral complex between a general transcription factor and virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number of molecules. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

11 pages, 1535 KiB

Open AccessArticle

Complex Mutation Pattern of Omicron BA.2: Evading Antibodies without Losing Receptor Interactions

by Saathvik R. Kannan, Austin N. Spratt, Kalicharan Sharma, Ramesh Goyal, Anders Sönnerborg, Subbu Apparsundaram, Christian L. Lorson, Siddappa N. Byrareddy and Kamal Singh

Int. J. Mol. Sci. 2022, 23(10), 5534; https://doi.org/10.3390/ijms23105534 - 16 May 2022

Cited by 11 | Viewed by 2591

Abstract

BA.2, a sublineage of Omicron BA.1, is now prominent in many parts of the world. Early reports have indicated that BA.2 is more infectious than BA.1. To gain insight into BA.2 mutation profile and the resulting impact of mutations on interactions with receptor [...] Read more.

BA.2, a sublineage of Omicron BA.1, is now prominent in many parts of the world. Early reports have indicated that BA.2 is more infectious than BA.1. To gain insight into BA.2 mutation profile and the resulting impact of mutations on interactions with receptor and/or monoclonal antibodies, we analyzed available sequences, structures of Spike/receptor and Spike/antibody complexes, and conducted molecular dynamics simulations. The results showed that BA.2 had 50 high-prevalent mutations, compared to 48 in BA.1. Additionally, 17 BA.1 mutations were not present in BA.2. Instead, BA.2 had 19 unique mutations and a signature Delta variant mutation (G142D). The BA.2 had 28 signature mutations in Spike, compared to 30 in BA.1. This was due to two revertant mutations, S446G and S496G, in the receptor-binding domain (RBD), making BA.2 somewhat similar to Wuhan-Hu-1 (WT), which had G446 and G496. The molecular dynamics simulations showed that the RBD consisting of G446/G496 was more stable than S446/S496 containing RBD. Thus, our analyses suggested that BA.2 evolved with novel mutations (i) to maintain receptor binding similar to WT, (ii) evade the antibody binding greater than BA.1, and (iii) acquire mutation of the Delta variant that may be associated with the high infectivity. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

Review

Jump to: Research

21 pages, 10371 KiB

Open AccessReview

Plant Coumarins with Anti-HIV Activity: Isolation and Mechanisms of Action

by Ainur D. Sharapov, Ramil F. Fatykhov, Igor A. Khalymbadzha, Grigory V. Zyryanov, Oleg N. Chupakhin and Mikhail V. Tsurkan

Int. J. Mol. Sci. 2023, 24(3), 2839; https://doi.org/10.3390/ijms24032839 - 2 Feb 2023

Cited by 19 | Viewed by 2290

Abstract

This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and [...] Read more.

This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

23 pages, 2002 KiB

Open AccessReview

The Fight against the Carcinogenic Epstein-Barr Virus: Gut Microbiota, Natural Medicines, and Beyond

by Radwa A. Eladwy, Hang Thi Vu, Ravi Shah, Chun Guang Li, Dennis Chang and Deep Jyoti Bhuyan

Int. J. Mol. Sci. 2023, 24(2), 1716; https://doi.org/10.3390/ijms24021716 - 15 Jan 2023

Cited by 5 | Viewed by 8206

Abstract

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), [...] Read more.

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), and hepatitis B and C viruses. EBV, a member of the human gamma herpesvirus family, is a double-stranded DNA virus and the primary cause of infectious mononucleosis. Most EBV infections cause no long-term complications. However, it was reported that EBV infection is responsible for around 200,000 malignancies worldwide every year. Currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection. Recently, the gut microbiota has been investigated for its pivotal roles in pathogen protection and regulating metabolic, endocrine, and immune functions. Several studies have investigated the efficacy of antiviral agents, gut microbial metabolites, and natural products against EBV infection. In this review, we aim to summarise and analyse the reported molecular mechanistic and clinical studies on the activities of gut microbial metabolites and natural medicines against carcinogenic viruses, with a particular emphasis on EBV. Gut microbial metabolites such as short-chain fatty acids were reported to activate the EBV lytic cycle, while bacteriocins, produced by Enterococcus durans strains, have shown antiviral properties. Furthermore, several natural products and dietary bioactive compounds, such as curcumin, epigallocatechin gallate, resveratrol, moronic acid, and andrographolide, have shown antiviral activity against EBV. In this review, we proposed several exciting future directions for research on carcinogenic viruses. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

18 pages, 8341 KiB

Open AccessReview

Triazavirin—A Novel Effective Antiviral Drug

by Oleg N. Chupakhin, Vladimir L. Rusinov, Mikhail V. Varaksin, Evgeny N. Ulomskiy, Konstantin V. Savateev, Ilya I. Butorin, Weijie Du, Zhiyong Sun and Valery N. Charushin

Int. J. Mol. Sci. 2022, 23(23), 14537; https://doi.org/10.3390/ijms232314537 - 22 Nov 2022

Cited by 9 | Viewed by 2260

Abstract

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has [...] Read more.

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

18 pages, 1657 KiB

Open AccessReview

Inhibition of Viral RNA-Dependent RNA Polymerases by Nucleoside Inhibitors: An Illustration of the Unity and Diversity of Mechanisms

by Sailen Barik

Int. J. Mol. Sci. 2022, 23(20), 12649; https://doi.org/10.3390/ijms232012649 - 21 Oct 2022

Cited by 3 | Viewed by 2165

Abstract

RNA-dependent RNA polymerase (RdRP) is essential for the replication and expression of RNA viral genomes. This class of viruses comprise a large number of highly pathogenic agents that infect essentially all species of plants and animals including humans. Infections often lead to epidemics [...] Read more.

RNA-dependent RNA polymerase (RdRP) is essential for the replication and expression of RNA viral genomes. This class of viruses comprise a large number of highly pathogenic agents that infect essentially all species of plants and animals including humans. Infections often lead to epidemics and pandemics that have remained largely out of control due to the lack of specific and reliable preventive and therapeutic regimens. This unmet medical need has led to the exploration of new antiviral targets, of which RdRP is a major one, due to the fact of its obligatory need in virus growth. Recent studies have demonstrated the ability of several synthetic nucleoside analogs to serve as mimics of the corresponding natural nucleosides. These mimics cause stalling/termination of RdRP, or misincorporation, preventing virus replication or promoting large-scale lethal mutations. Several such analogs have received clinical approval and are being routinely used in therapy. In parallel, the molecular structural basis of their inhibitory interactions with RdRP is being elucidated, revealing both traditional and novel mechanisms including a delayed chain termination effect. This review offers a molecular commentary on these mechanisms along with their clinical implications based on analyses of recent results, which should facilitate the rational design of structure-based antiviral drugs. Full article

(This article belongs to the Special Issue Antiviral Drugs and Virus Infection)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Antiviral Drugs and Virus Infection

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI