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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 11217

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Special Issue Editor

Prof. Dr. Takashi Okamoto

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Guest Editor

Department of Molecular and Cellular Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 4678601, Japan
Interests: HIV; transcriptin; signal transduction; NF-kB; cancer; rheumatoid arthritis; structure bioinformatics

Special Issue Information

Dear Colleagues,

In this era of advanced molecular biology and updated computer technology, various universal tools are becoming available for our scientific community with the accumulation of databases. These include databases of genomes, transcriptomes, proteomes, interactomes and protein 3D structures. We have attempted to set up a common platform for interdisciplinary as well as international discussions with regard to furthering understanding of biomedical processes and the novel development of specific therapies using these scientific assets. Since the computing power appears to double every 18–24 months (Moore’s law), each article/review in this Special Issue cannot refer to a final status. The will, however, document the notable milestones of each discipline. We hope this constellation of articles may stimulate the scientific minds of our readers and open up fruitful avenues for biomedical exploration into underdeveloped scientific research spaces.

The following is a list of research topics of interest to this Special Issue.

Protein–protein interactions (PPIs) vital for viral/microbial replication.
In silico drug screening.
Development of anti-HIV drugs that target gene expression.
Further application of computational chemistry for drug development.
Future perspectives.

Prof. Dr. Takashi Okamoto
Guest Editor

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Keywords

antimicrobial compounds
in silico drug screening
protein–protein interaction (PPI)
HIV transcription
structure bioinformatics
computer-assisted drug development

Published Papers (6 papers)

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Research

21 pages, 7983 KiB

Open AccessArticle

Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu

by Andreia E. S. Cunha, Rui J. S. Loureiro, Carlos J. V. Simões and Rui M. M. Brito

Int. J. Mol. Sci. 2023, 24(3), 2977; https://doi.org/10.3390/ijms24032977 - 3 Feb 2023

Cited by 1 | Viewed by 2004

Abstract

Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1’s role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein–protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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12 pages, 3773 KiB

Open AccessCommunication

Identification of Potent Zika Virus NS5 RNA-Dependent RNA Polymerase Inhibitors Combining Virtual Screening and Biological Assays

by Ying Chen, Xiangyin Chi, Hongjuan Zhang, Yu Zhang, Luyao Qiao, Jinwen Ding, Yanxing Han, Yuan Lin and Jiandong Jiang

Int. J. Mol. Sci. 2023, 24(3), 1900; https://doi.org/10.3390/ijms24031900 - 18 Jan 2023

Cited by 3 | Viewed by 1871

Abstract

The Zika virus (ZIKV) epidemic poses a significant threat to human health globally. Thus, there is an urgent need for developing effective anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp), a viral enzyme for viral replication, has been considered an attractive drug target. In this work, we screened an anti-infection compound library and a natural product library by virtual screening to identify potential candidates targeting RdRp. Then, five selected candidates were further applied for RdRp enzymatic analysis, cytotoxicity, and binding examination by SPR. Finally, posaconazole (POS) was confirmed to effectively inhibit both RdRp activity with an IC₅₀ of 4.29 μM and the ZIKV replication with an EC₅₀ of 0.59 μM. Moreover, POS was shown to reduce RdRp activity by binding with the key amino acid D666 through molecular docking and site-directed mutation analysis. For the first time, our work found that POS could inhibit ZIKV replication with a stronger inhibitory activity than chloroquine. This work also demonstrated fast anti-ZIKV screening for inhibitors of RdRp and provided POS as a potential anti-ZIKV agent. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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12 pages, 3601 KiB

Open AccessArticle

Antiviral Effect of Isoquercitrin against Influenza A Viral Infection via Modulating Hemagglutinin and Neuraminidase

by Won-Kyung Cho, Myong-Min Lee and Jin Yeul Ma

Int. J. Mol. Sci. 2022, 23(21), 13112; https://doi.org/10.3390/ijms232113112 - 28 Oct 2022

Cited by 9 | Viewed by 1652

Abstract

Isoquercitrin (IQC) is a component abundantly present in many plants and is known to have an anti-viral effect against various viruses. In this study, we demonstrate that IQC exhibits strong anti-influenza A virus infection, and its effect is closely related to the suppression of hemagglutinin (HA) and neuraminidase (NA) activities. We used green fluorescent protein-tagged Influenza A/PR/8/34 (H1N1), A/PR/8/34 (H1N1), and HBPV-VR-32 (H3N2) to evaluate the anti-IAV effect of IQC. The fluorescence microscopy and fluorescence-activated cell sorting analysis showed that IQC significantly decreases the levels of GFP expressed by IAV infection, dose-dependently. Consistent with that, IQC inhibited cytopathic effects by H1N1 or H3N2 IAV infection. Immunofluorescence analysis confirmed that IQC represses the IAV protein expression. Time-of-addition assay showed that IQC inhibits viral attachment and entry and exerts a strong virucidal effect during IAV infection. Hemagglutination assay confirmed that IQC affects IAV HA. Further, IQC potently reduced the NA activities of H1N1 and H3N2 IAV. Collectively, IQC prevents IAV infection at multi-stages via virucidal effects, inhibiting attachment, entry and viral release. Our results indicate that IQC could be developed as a potent antiviral drug to protect against influenza viral infection. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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14 pages, 12515 KiB

Open AccessArticle

Identification of Novel Nucleocapsid Chimeric Proteins Inhibiting HIV-1 Replication

by Hae-In Kim, Ga-Na Kim, Kyung-Lee Yu, Seong-Hyun Park and Ji Chang You

Int. J. Mol. Sci. 2022, 23(20), 12340; https://doi.org/10.3390/ijms232012340 - 15 Oct 2022

Cited by 1 | Viewed by 1207

Abstract

The positive transcription elongation factor b (P-TEFb) is an essential factor that induces transcription elongation and is also negatively regulated by the cellular factor HEXIM1. Previously, the chimeric protein HEXIM1-Tat (HT) was demonstrated to inhibit human immunodeficiency virus-1 (HIV)-1 transcription. In this study, we attempted to develop an improved antiviral protein that specifically binds viral RNA (vRNA) by fusing HT to HIV-1 nucleocapsid (NC). Thus, we synthesized NC-HEXIM1-Tat (NHT) and HEXIM1-Tat-NC (HTN). NHT and HTN inhibited virus proliferation more effectively than HT, and they did not attenuate the function of HT. Notably, NHT and HTN inhibited the infectivity of the progeny virus, whereas HT had no such effect. NHT and HTN selectively and effectively interacted with vRNA and inhibited the proper packaging of the HIV-1 genome. Taken together, our results illustrated that the novel NC-fused chimeric proteins NHT and HTN display novel mechanisms of anti-HIV effects by inhibiting both HIV-1 transcription and packaging. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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10 pages, 2890 KiB

Open AccessArticle

Resensitization of Fosfomycin-Resistant Escherichia coli Using the CRISPR System

by Haniel Siqueira Mortagua Walflor, Aline Rodrigues Castro Lucena, Felipe Francisco Tuon, Lia Carolina Soares Medeiros and Helisson Faoro

Int. J. Mol. Sci. 2022, 23(16), 9175; https://doi.org/10.3390/ijms23169175 - 16 Aug 2022

Cited by 4 | Viewed by 2072

Abstract

Antimicrobial resistance is a public health burden with worldwide impacts and was recently identified as one of the major causes of death in 2019. Fosfomycin is an antibiotic commonly used to treat urinary tract infections, and resistance to it in Enterobacteriaceae is mainly due to the metalloenzyme FosA3 encoded by the fosA3 gene. In this work, we adapted a CRISPR-Cas9 system named pRE-FOSA3 to restore the sensitivity of a fosA3⁺ Escherichia coli strain. The fosA3⁺ E. coli strain was generated by transforming synthetic fosA3 into a nonpathogenic E. coli TOP10. To mediate the fosA3 disruption, two guide RNAs (gRNAs) were selected that used conserved regions within the fosA3 sequence of more than 700 fosA3⁺ E. coli isolates, and the resensitization plasmid pRE-FOSA3 was assembled by cloning the gRNA into pCas9. gRNA_195 exhibited 100% efficiency in resensitizing the bacteria to fosfomycin. Additionally, the edited strain lost the ampicillin resistance encoded in the same plasmid containing the synthetic fosA3 gene, despite not being the CRISPR-Cas9 target, indicating plasmid clearance. The in vitro analysis presented here points to a path that can be explored to assist the development of effective alternative methods of treatment against fosA3⁺ bacteria. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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15 pages, 3871 KiB

Open AccessArticle

Simvastatin Inhibits Brucella abortus Invasion into RAW 264.7 Cells through Suppression of the Mevalonate Pathway and Promotes Host Immunity during Infection in a Mouse Model

by Trang Thi Nguyen, Heejin Kim, Tran Xuan Ngoc Huy, Wongi Min, Hujang Lee, Alisha Wehdnesday Bernardo Reyes, Johnhwa Lee and Suk Kim

Int. J. Mol. Sci. 2022, 23(15), 8337; https://doi.org/10.3390/ijms23158337 - 28 Jul 2022

Cited by 1 | Viewed by 1751

Abstract

Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase and has been found to have protective effects against several bacterial infections. In this study, we investigate the effects of simvastatin treatment on RAW 264.7 macrophage cells and ICR mice against Brucella (B.) abortus infections. The invasion assay revealed that simvastatin inhibited the Brucella invasion into macrophage cells by blocking the mevalonic pathway. The treatment of simvastatin enhanced the trafficking of Toll-like receptor 4 in membrane lipid raft microdomains, accompanied by the increased phosphorylation of its downstream signaling pathways, including JAK2 and MAPKs, upon =Brucella infection. Notably, the suppressive effect of simvastatin treatment on Brucella invasion was not dependent on the reduction of cholesterol synthesis but probably on the decline of farnesyl pyrophosphate and geranylgeranyl pyrophosphate synthesis. In addition to a direct brucellacidal ability, simvastatin administration showed increased cytokine TNF-α and differentiation of CD8⁺ T cells, accompanied by reduced bacterial survival in spleens of ICR mice. These data suggested the involvement of the mevalonate pathway in the phagocytosis of B. abortus into RAW 264.7 macrophage cells and the regulation of simvastatin on the host immune system against Brucella infections. Therefore, simvastatin is a potential candidate for studying alternative therapy against animal brucellosis. Full article

(This article belongs to the Special Issue Advanced Antiviral and Antimicrobial Drug Discovery)

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