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Viruses
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Viral Entry Pathways
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Viral Entry Pathways

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (15 October 2019) | Viewed by 93808

Special Issue Editors

Prof. Dr. Anthony V. Nicola

E-Mail Website
Guest Editor
Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
Interests: virology; virus-host interactions; viral entry; antivirals; herpesviruses; endocytosis; membrane fusion; viral glycoproteins
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lijun Rong

E-Mail Website
Guest Editor
College of Medicine, University of Illinois, Chicago, IL, USA
Interests: studying entry and replication mechanisms of viruses with pandemic potential, and developing antivirals
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lu Lu

E-Mail Website
Guest Editor
Key Laboratory of Medical Molecular Virology of Ministries of Health and Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
Interests: antivirals; mechanisms of viral entry; entry inhibitors; peptide inhibitors; vaccine; coronavirus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral entry is the first step of infection in the viral life cycle and an important antiviral target. This process is initiated by specific interactions between a virus protein(s) with host factors on the host cells, and followed by diverse pathways such as endocytosis, membrane fusion, and/or viral penetration to enter the target cells. Recent work using an integral approach of cell biology studies, live-cell imaging, structural biology, and systems biology has provided new insights into the multiple and subtly different pathways that viruses use to enter host cells.
In this Special Issue, we welcome submissions of research or review articles on recent advances in our understanding of viral entry pathways. Topics may include but are not limited to the cell and molecular biology of viral entry, virus–host interactions, cellular receptors, viral structures, and antivirals of both DNA and RNA viruses.

Prof. Dr. Anthony V. Nicola
Prof. Dr. Lijun Rong
Prof. Dr. Lu Lu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • viral entry pathways
  • endocytic entry
  • viral membrane fusion
  • viral penetration
  • virus-host interactions
  • virus receptor
  • viral entry inhibitor
  • antivirals

Published Papers (15 papers)

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Research

Jump to: Review

12 pages, 4310 KiB  
Article
Avian Flavivirus Enters BHK-21 Cells by a Low pH-Dependent Endosomal Pathway
by Abdul Sattar Baloch, Chunchun Liu, Xiaodong Liang, Yayun Liu, Jing Chen, Ruibing Cao and Bin Zhou
Viruses 2019, 11(12), 1112; https://0-doi-org.brum.beds.ac.uk/10.3390/v11121112 - 30 Nov 2019
Cited by 10 | Viewed by 3049
Abstract
Duck Tembusu virus (DTMUV), a pathogenic member of the Flavivirus family, was first discovered in the coastal provinces of South-Eastern China in 2010. Many previous reports have clearly shown that some Flaviviruses utilize several endocytic pathways to enter the host cells, however, the [...] Read more.
Duck Tembusu virus (DTMUV), a pathogenic member of the Flavivirus family, was first discovered in the coastal provinces of South-Eastern China in 2010. Many previous reports have clearly shown that some Flaviviruses utilize several endocytic pathways to enter the host cells, however, the detailed mechanism of DTMUV entry into BHK-21 cells, which is usually employed to produce commercial veterinary vaccines for DTMUV, as well as of other Flaviviruses by serial passages, is still unknown. In this study, DTMUV entry into BHK-21 cells was found to be inhibited by noncytotoxic concentrations of the agents chloroquine, NH4Cl, and Bafilomycin A1, which blocked the acidification of the endosomes. Inactivation of virions by acid pretreatment is a hallmark of viruses that utilize a low-pH-mediated entry pathway. Exposure of DTMUV virions to pH 5.0 in the absence of host cell membranes decreased entry into cells by 65%. Furthermore, DTMUV infection was significantly decreased by chlorpromazine treatment, or by knockdown of the clathrin heavy chain (CHC) through RNA interference, which suggested that DTMUV entry depends on clathrin. Taken together, these findings highlight that a low endosomal pH is an important route of entry for DTMUV. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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17 pages, 2601 KiB  
Article
Erythromycin Estolate Inhibits Zika Virus Infection by Blocking Viral Entry as a Viral Inactivator
by Xiaohuan Wang, Shuai Xia, Peng Zou and Lu Lu
Viruses 2019, 11(11), 1064; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111064 - 15 Nov 2019
Cited by 12 | Viewed by 4352
Abstract
Recently, Zika virus (ZIKV) has attracted much attention in consideration of its association with severe neurological complications including fetal microcephaly. However, there are currently no prophylactic vaccines or therapeutic drugs approved for clinical treatments of ZIKV infection. To determine the potential anti-ZIKV inhibitors, [...] Read more.
Recently, Zika virus (ZIKV) has attracted much attention in consideration of its association with severe neurological complications including fetal microcephaly. However, there are currently no prophylactic vaccines or therapeutic drugs approved for clinical treatments of ZIKV infection. To determine the potential anti-ZIKV inhibitors, we screened a library of clinical drugs with good safety profiles. Erythromycin estolate (Ery-Est), one of the macrolide antibiotics, was found to effectively inhibit ZIKV infection in different cell types and significantly protect A129 mice from ZIKV-associated neurological signs and mortality. Through further investigation, Ery-Est was verified to inhibit ZIKV entry by disrupting the integrity of the viral membrane which resulted in the loss of ZIKV infectivity. Furthermore, Ery-Est also showed inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Thus, Ery-Est may be a promising drug for patients with ZIKV infection, particularly pregnant women. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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18 pages, 1515 KiB  
Article
Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors
by Yaning Gao, Wanbo Tai, Ning Wang, Xiang Li, Shibo Jiang, Asim K. Debnath, Lanying Du and Shizhong Chen
Viruses 2019, 11(11), 1019; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111019 - 02 Nov 2019
Cited by 47 | Viewed by 4406
Abstract
Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a [...] Read more.
Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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Graphical abstract

19 pages, 2644 KiB  
Article
A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor
by Suiyi Tan, Wenjuan Li, Zhaofeng Li, Yujing Li, Jiangyan Luo, Liangzhentian Yu, Jie Yang, Mengjie Qiu, Hongyan Cheng, Wei Xu, Shibo Jiang, Lu Lu, Shuwen Liu and Weifeng Ma
Viruses 2019, 11(9), 874; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090874 - 18 Sep 2019
Cited by 8 | Viewed by 4147
Abstract
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological [...] Read more.
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the α-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell–cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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13 pages, 2685 KiB  
Article
Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action
by Chen Wang, Shuihong Cheng, Yuanyuan Zhang, Yibo Ding, Huihui Chong, Hui Xing, Shibo Jiang, Xuebing Li and Liying Ma
Viruses 2019, 11(9), 811; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090811 - 02 Sep 2019
Cited by 13 | Viewed by 3754
Abstract
The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their [...] Read more.
The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell–cell fusion with an effective concentration for 50% inhibition (EC50) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC50 of about 4–5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC50 of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t1/2) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t1/2 of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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21 pages, 4401 KiB  
Article
In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4
by Alexander M. Andrianov, Grigory I. Nikolaev, Yuri V. Kornoushenko, Wei Xu, Shibo Jiang and Alexander V. Tuzikov
Viruses 2019, 11(8), 746; https://0-doi-org.brum.beds.ac.uk/10.3390/v11080746 - 13 Aug 2019
Cited by 10 | Viewed by 3546
Abstract
Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of [...] Read more.
Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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21 pages, 6063 KiB  
Article
Conserved Residue Asn-145 in the C-Terminal Heptad Repeat Region of HIV-1 gp41 is Critical for Viral Fusion and Regulates the Antiviral Activity of Fusion Inhibitors
by Xiuzhu Geng, Zixuan Liu, Danwei Yu, Bo Qin, Yuanmei Zhu, Sheng Cui, Huihui Chong and Yuxian He
Viruses 2019, 11(7), 609; https://0-doi-org.brum.beds.ac.uk/10.3390/v11070609 - 03 Jul 2019
Cited by 5 | Viewed by 3904
Abstract
Entry of HIV-1 into target cells is mediated by its envelope (Env) glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41. Refolding of the gp41 N- and C-terminal heptad repeats (NHR and CHR) into a six-helix bundle (6-HB) conformation [...] Read more.
Entry of HIV-1 into target cells is mediated by its envelope (Env) glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41. Refolding of the gp41 N- and C-terminal heptad repeats (NHR and CHR) into a six-helix bundle (6-HB) conformation drives the viral and cellular membranes in close apposition and generates huge amounts of energy to overcome the kinetic barrier leading to membrane fusion. In this study, we focused on characterizing the structural and functional properties of a single Asn-145 residue, which locates at the middle CHR site of gp41 and is extremely conserved among all the HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates. By mutational analysis, we found that Asn-145 plays critical roles for Env-mediated cell-cell fusion and HIV-1 entry. As determined by circular dichroism (CD) spectroscopy and isothermal titration calorimetry (ITC), the substitution of Asn-145 with alanine (N145A) severely impaired the interactions between the NHR and CHR helices. Asn-145 was also verified to be important for the antiviral activity of CHR-derived peptide fusion inhibitors and served as a turn-point for the inhibitory potency. Intriguingly, Asn-145 could regulate the functionality of the M-T hook structure at the N-terminus of the inhibitors and displayed comparable activities with the C-terminal IDL anchor. Crystallographic studies further demonstrated the importance of Asn-145-mediated interhelical and intrahelical interactions in the 6-HB structure. Combined, the present results have provided valuable information for the structure-function relationship of HIV-1 gp41 and the structure-activity relationship of gp41-dependent fusion inhibitors. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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13 pages, 5434 KiB  
Article
Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus
by Shuofeng Yuan, Jasper Fuk-Woo Chan, Zi-Wei Ye, Lei Wen, Terance Gi-Wai Tsang, Jianli Cao, Jingjing Huang, Chris Chun-Yiu Chan, Kenn Ka-Heng Chik, Garnet Kwan-Yue Choi, Jian-Piao Cai, Feifei Yin, Hin Chu, Mifang Liang, Dong-Yan Jin and Kwok-Yung Yuen
Viruses 2019, 11(4), 385; https://0-doi-org.brum.beds.ac.uk/10.3390/v11040385 - 25 Apr 2019
Cited by 21 | Viewed by 6082
Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing [...] Read more.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing a two-tier test system to rapidly screen a Food and Drug Administration- (FDA)-approved drug library for drug compounds with anti-SFTSV activity in vitro. We identified five drug compounds that inhibited SFTSV replication at low micromolar concentrations, including hexachlorophene, triclosan, regorafenib, eltrombopag, and broxyquinoline. Among them, hexachlorophene was the most potent with an IC50 of 1.3 ± 0.3 µM and a selectivity index of 18.7. Mechanistic studies suggested that hexachlorophene was a virus entry inhibitor, which impaired SFTSV entry into host cells by interfering with cell membrane fusion. Molecular docking analysis predicted that the binding of hexachlorophene with the hydrophobic pocket between domain I and domain III of the SFTSV Gc glycoprotein was highly stable. The novel antiviral activity and mechanism of hexachlorophene in this study would facilitate the use of hexachlorophene as a lead compound to develop more entry inhibitors with higher anti-SFTSV potency and lower toxicity. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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Review

Jump to: Research

28 pages, 3442 KiB  
Review
Differential Features of Fusion Activation within the Paramyxoviridae
by Kristopher D. Azarm and Benhur Lee
Viruses 2020, 12(2), 161; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020161 - 30 Jan 2020
Cited by 21 | Viewed by 5575
Abstract
Paramyxovirus (PMV) entry requires the coordinated action of two envelope glycoproteins, the receptor binding protein (RBP) and fusion protein (F). The sequence of events that occurs during the PMV entry process is tightly regulated. This regulation ensures entry will only initiate when the [...] Read more.
Paramyxovirus (PMV) entry requires the coordinated action of two envelope glycoproteins, the receptor binding protein (RBP) and fusion protein (F). The sequence of events that occurs during the PMV entry process is tightly regulated. This regulation ensures entry will only initiate when the virion is in the vicinity of a target cell membrane. Here, we review recent structural and mechanistic studies to delineate the entry features that are shared and distinct amongst the Paramyxoviridae. In general, we observe overarching distinctions between the protein-using RBPs and the sialic acid- (SA-) using RBPs, including how their stalk domains differentially trigger F. Moreover, through sequence comparisons, we identify greater structural and functional conservation amongst the PMV fusion proteins, as compared to the RBPs. When examining the relative contributions to sequence conservation of the globular head versus stalk domains of the RBP, we observe that, for the protein-using PMVs, the stalk domains exhibit higher conservation and find the opposite trend is true for SA-using PMVs. A better understanding of conserved and distinct features that govern the entry of protein-using versus SA-using PMVs will inform the rational design of broader spectrum therapeutics that impede this process. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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17 pages, 1527 KiB  
Review
Towards Understanding KSHV Fusion and Entry
by Stephen J. Dollery
Viruses 2019, 11(11), 1073; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111073 - 18 Nov 2019
Cited by 20 | Viewed by 5052
Abstract
How viruses enter cells is of critical importance to pathogenesis in the host and for treatment strategies. Over the last several years, the herpesvirus field has made numerous and thoroughly fascinating discoveries about the entry of alpha-, beta-, and gamma-herpesviruses, giving rise to [...] Read more.
How viruses enter cells is of critical importance to pathogenesis in the host and for treatment strategies. Over the last several years, the herpesvirus field has made numerous and thoroughly fascinating discoveries about the entry of alpha-, beta-, and gamma-herpesviruses, giving rise to knowledge of entry at the amino acid level and the realization that, in some cases, researchers had overlooked whole sets of molecules essential for entry into critical cell types. Herpesviruses come equipped with multiple envelope glycoproteins which have several roles in many aspects of infection. For herpesvirus entry, it is usual that a collective of glycoproteins is involved in attachment to the cell surface, specific interactions then take place between viral glycoproteins and host cell receptors, and then molecular interactions and triggers occur, ultimately leading to viral envelope fusion with the host cell membrane. The fact that there are multiple cell and virus molecules involved with the build-up to fusion enhances the diversity and specificity of target cell types, the cellular entry pathways the virus commandeers, and the final triggers of fusion. This review will examine discoveries relating to how Kaposi’s sarcoma-associated herpesvirus (KSHV) encounters and binds to critical cell types, how cells internalize the virus, and how the fusion may occur between the viral membrane and the host cell membrane. Particular focus is given to viral glycoproteins and what is known about their mechanisms of action. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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15 pages, 2333 KiB  
Review
The Symmetry of Viral Sialic Acid Binding Sites–Implications for Antiviral Strategies
by Nils H. Rustmeier, Michael Strebl and Thilo Stehle
Viruses 2019, 11(10), 947; https://0-doi-org.brum.beds.ac.uk/10.3390/v11100947 - 14 Oct 2019
Cited by 7 | Viewed by 4988
Abstract
Virus infections are initiated by the attachment of the viral particle to protein or carbohydrate receptors on the host cell. Sialic acid-bearing glycan structures are prominently displayed at the cell surface, and, consequently, these structures can function as receptors for a large number [...] Read more.
Virus infections are initiated by the attachment of the viral particle to protein or carbohydrate receptors on the host cell. Sialic acid-bearing glycan structures are prominently displayed at the cell surface, and, consequently, these structures can function as receptors for a large number of diverse viruses. Structural biology research has helped to establish the molecular bases for many virus–sialic acid interactions. Due to the icosahedral 532 point group symmetry that underlies many viral capsids, the receptor binding sites are frequently arranged in a highly symmetric fashion and linked by five-fold, three-fold, or two-fold rotation axes. For the inhibition of viral attachment, one emerging strategy is based on developing multivalent sialic acid-based inhibitors that can simultaneously engage several of these binding sites, thus binding viral capsids with high avidity. In this review, we will evaluate the structures of non-enveloped virus capsid proteins bound to sialylated glycan receptors and discuss the potential of these structures for the development of potent antiviral attachment inhibitors. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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11 pages, 1341 KiB  
Review
SV40 Hijacks Cellular Transport, Membrane Penetration, and Disassembly Machineries to Promote Infection
by Yu-Jie Chen, Xiaofang Liu and Billy Tsai
Viruses 2019, 11(10), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/v11100917 - 05 Oct 2019
Cited by 23 | Viewed by 5443
Abstract
During entry, a virus must be transported through the endomembrane system of the host cell, penetrate a cellular membrane, and undergo capsid disassembly, to reach the cytosol and often the nucleus in order to cause infection. To do so requires the virus to [...] Read more.
During entry, a virus must be transported through the endomembrane system of the host cell, penetrate a cellular membrane, and undergo capsid disassembly, to reach the cytosol and often the nucleus in order to cause infection. To do so requires the virus to coordinately exploit the action of cellular membrane transport, penetration, and disassembly machineries. How this is accomplished remains enigmatic for many viruses, especially for viruses belonging to the nonenveloped virus family. In this review, we present the current model describing infectious entry of the nonenveloped polyomavirus (PyV) SV40. Insights from SV40 entry are likely to provide strategies to combat PyV-induced diseases, and to illuminate cellular trafficking, membrane transport, and disassembly mechanisms. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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19 pages, 4336 KiB  
Review
The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases
by Gonzalo Izaguirre
Viruses 2019, 11(9), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090837 - 09 Sep 2019
Cited by 107 | Viewed by 10369
Abstract
A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly [...] Read more.
A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is when some viruses become reactive with PCs that they may develop high pathogenicity. Besides reacting with furin, some viruses may also react with the PCs of the other specificity group constituted by PC4/PC5/PACE4/PC7. The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses. A wide variety of PC inhibitors have been developed and tested for their antiviral activity in cell-based assays. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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35 pages, 1560 KiB  
Review
Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41
by Jing Pu, Qian Wang, Wei Xu, Lu Lu and Shibo Jiang
Viruses 2019, 11(8), 705; https://0-doi-org.brum.beds.ac.uk/10.3390/v11080705 - 01 Aug 2019
Cited by 33 | Viewed by 13650
Abstract
Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of [...] Read more.
Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV entry inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV entry inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV entry inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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13 pages, 1022 KiB  
Review
Competitive Cooperation of Hemagglutinin and Neuraminidase during Influenza A Virus Entry
by Ruikun Du, Qinghua Cui and Lijun Rong
Viruses 2019, 11(5), 458; https://0-doi-org.brum.beds.ac.uk/10.3390/v11050458 - 20 May 2019
Cited by 49 | Viewed by 13818
Abstract
The hemagglutinin (HA) and neuraminidase (NA) of influenza A virus possess antagonistic activities on interaction with sialic acid (SA), which is the receptor for virus attachment. HA binds SA through its receptor-binding sites, while NA is a receptor-destroying enzyme by removing SAs. The [...] Read more.
The hemagglutinin (HA) and neuraminidase (NA) of influenza A virus possess antagonistic activities on interaction with sialic acid (SA), which is the receptor for virus attachment. HA binds SA through its receptor-binding sites, while NA is a receptor-destroying enzyme by removing SAs. The function of HA during virus entry has been extensively investigated, however, examination of NA has long been focused to its role in the exit of progeny virus from infected cells, and the role of NA in the entry process is still under-appreciated. This review summarizes the current understanding of the roles of HA and NA in relation to each other during virus entry. Full article
(This article belongs to the Special Issue Viral Entry Pathways)
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