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16 pages, 7569 KiB

Open AccessArticle

Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations

by Zixuan Zhao, Yinghong Ma, Xiangyuan Li, Susan L. Morris-Natschke, Zhaocui Sun, Zhonghao Sun, Guoxu Ma, Zhengqi Dong, Xiaohong Zhao, Meihua Yang, Xudong Xu, Kuohsiung Lee, Haifeng Wu and Chinho Chen

Int. J. Mol. Sci. 2023, 24(2), 1430; https://doi.org/10.3390/ijms24021430 - 11 Jan 2023

Cited by 6 | Viewed by 2508

Abstract

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as [...] Read more.

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3′,3′-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1_NL4-3 with an EC₅₀ value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r² = 0.99, q² = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents. Full article

(This article belongs to the Section Molecular Informatics)

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20 pages, 943 KiB

Open AccessReview

Visualization of Retroviral Gag-Genomic RNA Cellular Interactions Leading to Genome Encapsidation and Viral Assembly: An Overview

by Serena Bernacchi

Viruses 2022, 14(2), 324; https://doi.org/10.3390/v14020324 - 5 Feb 2022

Cited by 4 | Viewed by 3572

Abstract

Retroviruses must selectively recognize their unspliced RNA genome (gRNA) among abundant cellular and spliced viral RNAs to assemble into newly formed viral particles. Retroviral gRNA packaging is governed by Gag precursors that also orchestrate all the aspects of viral assembly. Retroviral life cycles, [...] Read more.

Retroviruses must selectively recognize their unspliced RNA genome (gRNA) among abundant cellular and spliced viral RNAs to assemble into newly formed viral particles. Retroviral gRNA packaging is governed by Gag precursors that also orchestrate all the aspects of viral assembly. Retroviral life cycles, and especially the HIV-1 one, have been previously extensively analyzed by several methods, most of them based on molecular biology and biochemistry approaches. Despite these efforts, the spatio-temporal mechanisms leading to gRNA packaging and viral assembly are only partially understood. Nevertheless, in these last decades, progress in novel bioimaging microscopic approaches (as FFS, FRAP, TIRF, and wide-field microscopy) have allowed for the tracking of retroviral Gag and gRNA in living cells, thus providing important insights at high spatial and temporal resolution of the events regulating the late phases of the retroviral life cycle. Here, the implementation of these recent bioimaging tools based on highly performing strategies to label fluorescent macromolecules is described. This report also summarizes recent gains in the current understanding of the mechanisms employed by retroviral Gag polyproteins to regulate molecular mechanisms enabling gRNA packaging and the formation of retroviral particles, highlighting variations and similarities among the different retroviruses. Full article

(This article belongs to the Special Issue RNA Packaging 2.0)

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20 pages, 2279 KiB

Open AccessReview

Importance of Viral Late Domains in Budding and Release of Enveloped RNA Viruses

by Lisa Welker, Jean-Christophe Paillart and Serena Bernacchi

Viruses 2021, 13(8), 1559; https://doi.org/10.3390/v13081559 - 6 Aug 2021

Cited by 22 | Viewed by 5009

Abstract

Late assembly (L) domains are conserved sequences that are necessary for the late steps of viral replication, acting like cellular adaptors to engage the ESCRT membrane fission machinery that promote virion release. These short sequences, whose mutation or deletion produce the accumulation of [...] Read more.

Late assembly (L) domains are conserved sequences that are necessary for the late steps of viral replication, acting like cellular adaptors to engage the ESCRT membrane fission machinery that promote virion release. These short sequences, whose mutation or deletion produce the accumulation of immature virions at the plasma membrane, were firstly identified within retroviral Gag precursors, and in a further step, also in structural proteins of many other enveloped RNA viruses including arenaviruses, filoviruses, rhabdoviruses, reoviruses, and paramyxoviruses. Three classes of L domains have been identified thus far (PT/SAP, YPXnL/LXXLF, and PPxY), even if it has recently been suggested that other motifs could act as L domains. Here, we summarize the current state of knowledge of the different types of L domains and their cellular partners in the budding events of RNA viruses, with a particular focus on retroviruses. Full article

(This article belongs to the Special Issue RNA Viruses and Membranes)

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19 pages, 3897 KiB

Open AccessArticle

Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT)

by Jerry Joe E. K. Harrison, Steve Tuske, Kalyan Das, Francesc X. Ruiz, Joseph D. Bauman, Paul L. Boyer, Jeffrey J. DeStefano, Stephen H. Hughes and Eddy Arnold

Viruses 2021, 13(8), 1495; https://doi.org/10.3390/v13081495 - 29 Jul 2021

Cited by 6 | Viewed by 2838

Abstract

In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy viruses (FVs) express Pol separately from Gag and, when Pol is processed, only the IN domain is [...] Read more.

In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy viruses (FVs) express Pol separately from Gag and, when Pol is processed, only the IN domain is released. Here, we report a 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV (PFV) that can carry out both proteolytic processing and reverse transcription but is in a configuration not competent for proteolytic or polymerase activity. PFV PR-RT is monomeric and the architecture of PFV PR is similar to one of the subunits of HIV-1 PR, which is a dimer. There is a C-terminal extension of PFV PR (101-145) that consists of two helices which are adjacent to the base of the RT palm subdomain, and anchors PR to RT. The polymerase domain of PFV RT consists of fingers, palm, thumb, and connection subdomains whose spatial arrangements are similar to the p51 subunit of HIV-1 RT. The RNase H and polymerase domains of PFV RT are connected by flexible linkers. Significant spatial and conformational (sub)domain rearrangements are therefore required for nucleic acid binding. The structure of PFV PR-RT provides insights into the conformational maturation of retroviral Pol polyproteins. Full article

(This article belongs to the Section Animal Viruses)

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16 pages, 970 KiB

Open AccessPerspective

Across the Hall from Pioneers

by Alan Rein

Viruses 2021, 13(3), 491; https://doi.org/10.3390/v13030491 - 16 Mar 2021

Cited by 4 | Viewed by 2081

Abstract

I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab made groundbreaking discoveries on retroviral proteins during that time, including many features that [...] Read more.

I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab made groundbreaking discoveries on retroviral proteins during that time, including many features that could not have been inferred or anticipated from straightforward sequence information. Building on the Oroszlan lab results, my colleagues and I demonstrated that the zinc fingers in nucleocapsid proteins play a crucial role in genomic RNA encapsidation; that the N-terminal myristylation of the Gag proteins of many retroviruses is important for their association with the plasma membrane before particle assembly is completed; and that gammaretroviruses initially synthesize their Env protein as an inactive precursor and then truncate the cytoplasmic tail of the transmembrane protein, activating Env fusogenicity, during virus maturation. We also elucidated several aspects of the mechanism of translational suppression in pol gene expression in gammaretroviruses; amazingly, this is a fundamentally different mechanism of suppression from that in most other retroviral genera. Full article

(This article belongs to the Special Issue In Memory of Stephen Oroszlan)

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26 pages, 8815 KiB

Open AccessReview

Post-Translational Modifications of Retroviral HIV-1 Gag Precursors: An Overview of Their Biological Role

by Charlotte Bussienne, Roland Marquet, Jean-Christophe Paillart and Serena Bernacchi

Int. J. Mol. Sci. 2021, 22(6), 2871; https://doi.org/10.3390/ijms22062871 - 11 Mar 2021

Cited by 14 | Viewed by 5289

Abstract

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also [...] Read more.

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also contribute to the cellular response to viral infections. All domains of the human immunodeficiency virus type 1 (HIV-1) Gag precursor of 55-kDa (Pr55^Gag), which is the central actor for viral RNA specific recruitment and genome packaging, are post-translationally modified. In this review, we summarize the current knowledge about HIV-1 Pr55^Gag PTMs such as myristoylation, phosphorylation, ubiquitination, sumoylation, methylation, and ISGylation in order to figure out how these modifications affect the precursor functions and viral replication. Indeed, in HIV-1, PTMs regulate the precursor trafficking between cell compartments and its anchoring at the plasma membrane, where viral assembly occurs. Interestingly, PTMs also allow Pr55^Gag to hijack the cell machinery to achieve viral budding as they drive recognition between viral proteins or cellular components such as the ESCRT machinery. Finally, we will describe and compare PTMs of several other retroviral Gag proteins to give a global overview of their role in the retroviral life cycle. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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22 pages, 3680 KiB

Open AccessArticle

PF74 and Its Novel Derivatives Stabilize Hexameric Lattice of HIV-1 Mature-Like Particles

by Alžběta Dostálková, Kryštof Škach, Filip Kaufman, Ivana Křížová, Romana Hadravová, Martin Flegel, Tomáš Ruml, Richard Hrabal and Michaela Rumlová

Molecules 2020, 25(8), 1895; https://doi.org/10.3390/molecules25081895 - 20 Apr 2020

Cited by 9 | Viewed by 3546

Abstract

A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part [...] Read more.

A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part of the Gag polyprotein precursor, facilitates protein–protein interactions that lead to the assembly of immature particles. Following protease activation and Gag polyprotein processing, CA also drives the assembly of the mature viral core. In the early stage of infection, the role of the CA protein is distinct. It controls the disassembly of the mature CA hexameric lattice i.e., uncoating, which is critical for the reverse transcription of the single-stranded RNA genome into double stranded DNA. These properties make CA a very attractive target for small molecule functioning as inhibitors of HIV-1 particle assembly and/or disassembly. Of these, inhibitors containing the PF74 scaffold have been extensively studied. In this study, we reported a series of modifications of the PF74 molecule and its characterization through a combination of biochemical and structural approaches. Our data supported the hypothesis that PF74 stabilizes the mature HIV-1 CA hexameric lattice. We identified derivatives with a higher in vitro stabilization activity in comparison to the original PF74 molecule. Full article

(This article belongs to the Section Molecular Structure)

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16 pages, 1922 KiB

Open AccessReview

Properties and Functions of Feline Immunodeficiency Virus Gag Domains in Virion Assembly and Budding

by Silvia A. González and José L. Affranchino

Viruses 2018, 10(5), 261; https://doi.org/10.3390/v10050261 - 16 May 2018

Cited by 8 | Viewed by 4713

Abstract

Feline immunodeficiency virus (FIV) is an important cat pathogen worldwide whose biological and pathophysiological properties resemble those of human immunodeficiency virus type 1 (HIV-1). Therefore, the study of FIV not only benefits its natural host but is also useful for the development of [...] Read more.

Feline immunodeficiency virus (FIV) is an important cat pathogen worldwide whose biological and pathophysiological properties resemble those of human immunodeficiency virus type 1 (HIV-1). Therefore, the study of FIV not only benefits its natural host but is also useful for the development of antiviral strategies directed against HIV-1 infections in humans. FIV assembly results from the multimerization of a single but complex viral polypeptide, the Gag precursor. In this review, we will first give an overview of the current knowledge of the proteins encoded by the FIV pol, env, rev, vif, and orf-A genes, and then we will describe and discuss in detail the critical roles that each of the FIV Gag domains plays in virion morphogenesis. Since retroviral assembly is an attractive target for therapeutic interventions, gaining a better understanding of this process is highly desirable. Full article

(This article belongs to the Special Issue Nonprimate Lentivirus)

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