scholarly journals Fullerene Derivatives Prevent Packaging of Viral Genomic RNA into HIV-1 Particles by Binding Nucleocapsid Protein

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2451
Author(s):  
Ivana Křížová ◽  
Alžběta Dostálková ◽  
Edison Castro ◽  
Jan Prchal ◽  
Romana Hadravová ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Biological Activities ◽  
Reverse Transcriptase Activity ◽  
Genomic Rna ◽  
Rna Packaging ◽  
Fullerene Derivatives ◽  
Viral Genomic Rna ◽  
Anti Hiv ◽  
Hiv 1

Fullerene derivatives with hydrophilic substituents have been shown to exhibit a range of biological activities, including antiviral ones. For a long time, the anti-HIV activity of fullerene derivatives was believed to be due to their binding into the hydrophobic pocket of HIV-1 protease, thereby blocking its activity. Recent work, however, brought new evidence of a novel, protease-independent mechanism of fullerene derivatives’ action. We studied in more detail the mechanism of the anti-HIV-1 activity of N,N-dimethyl[70]fulleropyrrolidinium iodide fullerene derivatives. By using a combination of in vitro and cell-based approaches, we showed that these C70 derivatives inhibited neither HIV-1 protease nor HIV-1 maturation. Instead, our data indicate effects of fullerene C70 derivatives on viral genomic RNA packaging and HIV-1 cDNA synthesis during reverse transcription—without impairing reverse transcriptase activity though. Molecularly, this could be explained by a strong binding affinity of these fullerene derivatives to HIV-1 nucleocapsid domain, preventing its proper interaction with viral genomic RNA, thereby blocking reverse transcription and HIV-1 infectivity. Moreover, the fullerene derivatives’ oxidative activity and fluorescence quenching, which could be one of the reasons for the inconsistency among reported anti-HIV-1 mechanisms, are discussed herein.

scholarly journals Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity

2016 ◽  
Vol 60 (10) ◽  
pp. 5731-5741 ◽  
Author(s):  
Zachary S. Martinez ◽  
Edison Castro ◽  
Chang-Soo Seong ◽  
Maira R. Cerón ◽  
Luis Echegoyen ◽  
...  
Keyword(s):  
T Cells ◽  
Life Cycle ◽  
Reverse Transcriptase ◽  
Immunoblot Analysis ◽  
Reverse Transcriptase Activity ◽  
Rna Packaging ◽  
Fullerene Derivatives ◽  
Contrast Analysis ◽  
Hiv 1

ABSTRACTThree compounds (1, 2, and 3) previously reported to inhibit HIV-1 replication and/orin vitroactivity of reverse transcriptase were studied, but only fullerene derivatives 1 and 2 showed strong antiviral activity on the replication of HIV-1 in human CD4+T cells. However, these compounds did not inhibit infection by single-round infection vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped viruses, indicating no effect on the early steps of the viral life cycle. In contrast, analysis of single-round infection VSV-G-pseudotyped HIV-1 produced in the presence of compound 1 or 2 showed a complete lack of infectivity in human CD4+T cells, suggesting that the late stages of the HIV-1 life cycle were affected. Quantification of virion-associated viral RNA and p24 indicates that RNA packaging and viral production were unremarkable in these viruses. However, Gag and Gag-Pol processing was affected, as evidenced by immunoblot analysis with an anti-p24 antibody and the measurement of virion-associated reverse transcriptase activity, ratifying the effect of the fullerene derivatives on virion maturation of the HIV-1 life cycle. Surprisingly, fullerenes 1 and 2 did not inhibit HIV-1 protease in anin vitroassay at the doses that potently blocked viral infectivity, suggesting a protease-independent mechanism of action. Highlighting the potential therapeutic relevance of fullerene derivatives, these compounds block infection by HIV-1 resistant to protease and maturation inhibitors.

scholarly journals Distinct binding interactions of HIV-1 Gag to Psi and non-Psi RNAs: Implications for viral genomic RNA packaging

RNA ◽  
2013 ◽  
Vol 19 (8) ◽  
pp. 1078-1088 ◽  
Author(s):  
J. A. Webb ◽  
C. P. Jones ◽  
L. J. Parent ◽  
I. Rouzina ◽  
K. Musier-Forsyth
Keyword(s):  
Genomic Rna ◽  
Rna Packaging ◽  
Binding Interactions ◽  
Viral Genomic Rna ◽  
Hiv 1

scholarly journals Association of Human Immunodeficiency Virus Type 1 Vif with RNA and Its Role in Reverse Transcription

2000 ◽  
Vol 74 (19) ◽  
pp. 8938-8945 ◽  
Author(s):  
Markus Dettenhofer ◽  
Shan Cen ◽  
Bradley A. Carlson ◽  
Lawrence Kleiman ◽  
Xiao-Fang Yu
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcription ◽  
Genomic Rna ◽  
Immunodeficiency Virus ◽  
Viral Genomic Rna ◽  
Hiv 1

ABSTRACT The vif gene of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication, although the functional target of Vif remains elusive. HIV-1 vif mutant virions derived from nonpermissive H9 cells displayed no significant differences in the amount, ratio, or integrity of their protein composition relative to an isogenic wild-type virion. The amounts of the virion-associated viral genomic RNA and tRNA3 Lyswere additionally present at normal levels in vif mutant virions. We demonstrate that Vif associates with RNA in vitro as well as with viral genomic RNA in virus-infected cells. A functionally conserved lentivirus Vif motif was found in the double-stranded RNA binding domain of Xenopus laevis, Xlrbpa. The natural intravirion reverse transcriptase products were markedly reduced invif mutant virions. Moreover, purified vifmutant genomic RNA-primer tRNA complexes displayed severe defects in the initiation of reverse transcription with recombinant reverse transcriptase. These data point to a novel role for Vif in the regulation of efficient reverse transcription through modulation of the virion nucleic acid components.

Differential in vitro Anti-HIV Activity of Natural Lignans

1990 ◽  
Vol 45 (11-12) ◽  
pp. 1215-1221 ◽  
Author(s):  
Heinz C Schröder ◽  
Helmut Merz ◽  
Renate Steffen ◽  
Werner E. G. Müller ◽  
Prem S. Sarin ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Reverse Transcriptase Activity ◽  
Cell System ◽  
Dna Topoisomerase ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Molecular Mechanism Of Action ◽  
Anti Hiv ◽  
Hiv 1

Abstract Two naturally occurring lignanolides, isolated from the tropical climbing shrub Ipomoea cairica, (-)-arctigen in and (-)-trachelogen in , were found to inhibit strongly replication of human immunodeficiency virus type 1 (HIV-1; strain HTLV-III B) in vitro. At a concentration of 0.5 (μм , (-)-arctigenin and (-)-trachelogenin inhibited the expression of HIV-1 proteins p 17 and p24 by 80 -90 % and 60 -70 % , respectively. The reverse transcriptase activity in the cul­ture fluids was reduced by 80 -90 % when the cells (HTLV-III B/H 9) were cultivated in the presence of 0.5 μм (-)-arctigen in or 1 μм (-)-trachelogenin . At the same concentrations, the formation of syncytia in the HTLV-III B/H 9-Jurkat cell system was inhibited by the compounds by more than 80%. A series of other lignan type compounds displayed no anti-HIV activity. Studying the molecular mechanism of action of (-)-arctigenin and (-)-trachelogenin we found that both compounds are efficient inhibitors of the nuclear matrix-associated DNA topoisomerase II activity, particularly of the enzyme from HIV -1-infected cells. Our results suggest that both compounds prevent the increase of topoisomerase II activity, involved in virus replication, after infection of cells with HIV -1.

scholarly journals MoMuLV and HIV-1 Nucleocapsid Proteins Have a Common Role in Genomic RNA Packaging but Different in Late Reverse Transcription

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51534 ◽  
Author(s):  
Célia Chamontin ◽  
Bing Yu ◽  
Pierre-Jean Racine ◽  
Jena-Luc Darlix ◽  
Marylène Mougel
Keyword(s):  
Reverse Transcription ◽  
Genomic Rna ◽  
Rna Packaging ◽  
Nucleocapsid Proteins ◽  
Hiv 1

scholarly journals HIV-1 integrase binding to genomic RNA 5′-UTR induces local structural changes in vitro and in virio

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shuohui Liu ◽  
Pratibha C. Koneru ◽  
Wen Li ◽  
Chathuri Pathirage ◽  
Alan N. Engelman ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Structural Changes ◽  
Genomic Rna ◽  
Packaging Signal ◽  
Virus Particles ◽  
Structure Changes ◽  
Apical Loop ◽  
Viral Genomic Rna ◽  
Hiv 1

Abstract Background During HIV-1 maturation, Gag and Gag-Pol polyproteins are proteolytically cleaved and the capsid protein polymerizes to form the honeycomb capsid lattice. HIV-1 integrase (IN) binds the viral genomic RNA (gRNA) and impairment of IN-gRNA binding leads to mis-localization of the nucleocapsid protein (NC)-condensed viral ribonucleoprotein complex outside the capsid core. IN and NC were previously demonstrated to bind to the gRNA in an orthogonal manner in virio; however, the effect of IN binding alone or simultaneous binding of both proteins on gRNA structure is not yet well understood. Results Using crosslinking-coupled selective 2′-hydroxyl acylation analyzed by primer extension (XL-SHAPE), we characterized the interaction of IN and NC with the HIV-1 gRNA 5′-untranslated region (5′-UTR). NC preferentially bound to the packaging signal (Psi) and a UG-rich region in U5, irrespective of the presence of IN. IN alone also bound to Psi but pre-incubation with NC largely abolished this interaction. In contrast, IN specifically bound to and affected the nucleotide (nt) dynamics of the apical loop of the transactivation response element (TAR) and the polyA hairpin even in the presence of NC. SHAPE probing of the 5′-UTR RNA in virions produced from allosteric IN inhibitor (ALLINI)-treated cells revealed that while the global secondary structure of the 5′-UTR remained unaltered, the inhibitor treatment induced local reactivity differences, including changes in the apical loop of TAR that are consistent with the in vitro results. Conclusions Overall, the binding interactions of NC and IN with the 5′-UTR are largely orthogonal in vitro. This study, together with previous probing experiments, suggests that IN and NC binding in vitro and in virio lead to only local structural changes in the regions of the 5′-UTR probed here. Accordingly, disruption of IN-gRNA binding by ALLINI treatment results in local rather than global secondary structure changes of the 5′-UTR in eccentric virus particles. Graphical Abstract

scholarly journals Sequence-specific interaction between HIV-1 matrix protein and viral genomic RNA revealed by in vitro genetic selection

RNA ◽  
2001 ◽  
Vol 7 (4) ◽  
pp. 576-584 ◽  
Author(s):  
PRAKASH PUROHIT ◽  
STEFAN DUPONT ◽  
MARIO STEVENSON ◽  
MICHAEL R. GREEN
Keyword(s):  
Matrix Protein ◽  
Specific Interaction ◽  
Genetic Selection ◽  
Genomic Rna ◽  
Viral Genomic Rna ◽  
Hiv 1

In vitro Anti-HIV and Antimicrobial Activities of a Halogenated Monoterpene from a Namibian Plocamium Species of Marine Algae

2020 ◽  
Vol 16 (3) ◽  
pp. 363-367
Author(s):  
Aina N. Shiyanga ◽  
Michael Knott ◽  
Petrina Kapewangolo
Keyword(s):  
Antibacterial Activity ◽  
Reverse Transcriptase ◽  
Biological Activities ◽  
Red Alga ◽  
Diffusion Method ◽  
Klebsiella Pneumonia ◽  
Halogenated Monoterpenes ◽  
Anti Hiv ◽  
Hiv 1

Background: The marine red alga Plocamium naturally produces halogenated monoterpenes with varied biological activities. In our continuing efforts to discover new lead compounds for the treatment of HIV/AIDS as well as novel antibacterial compounds, various Namibian Plocamium species have been investigated. Methods: A rare but known compound namely 1E,3R,4S,5E,7Z-1-bromo-3,4,8-trichloro-7- (dichloromethyl)-3-methylocta-1,5,7-triene (1) was isolated from a Namibian Plocamium red alga. The anti-HIV activity of compound 1 was investigated against three HIV enzymes namely, HIV protease, reverse transcriptase and integrase. In addition, compound 1 was also screened for antibacterial activity against selected microbes using the disc diffusion method. Results: Compound 1 demonstrated selective in vitro inhibition against HIV-1 integrase with a 50% inhibition concentration of <0.06 mM. Weak inhibitory activity was observed against HIV-1 reverse transcriptase and protease. Compound 1 also showed antibacterial activity against Staphylococcus aureus (ATCC 25923), Alcaligenes faecalis (ATCC 8750) and Serratia marcescens (ATCC 8100) with MIC values of 0.65 mM, and 1.29 mM for Klebsiella pneumonia (ATCC 13883). Conclusion: The results of this study highlight the potential of halogenated monoterpenes from red seaweed as possible leads in the development of new anti-HIV and antimicrobial pharmaceuticals.

Novel 4-Oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic Acid Derivatives as HIV-1 Integrase Inhibitors: Synthesis, Docking studies, Molecular Dynamics Simulation and Biological Activities.

2020 ◽  
Vol 16 ◽  
Author(s):  
Elnaz Ebrahim Zadeh ◽  
Rouhollah Vahabpour ◽  
Amirreza Dowlati Beirami ◽  
Zahra Hajimahdi ◽  
Afshin Zarghi
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Carboxylic Acid ◽  
Biological Activities ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Lead Compounds ◽  
Anti Hiv ◽  
Hiv 1

Background: HIV-1 integrase (IN) has been considered as an important target for the development of novel antiHIV-1 drugs. Objective: The aim of study is to design a novel groups of HIV IN inhibitors Method: In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole -diketoacids as a well-known group of IN inhibitors. Results: Based on in-vitro anti-HIV-1 activity in cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC50 values of 4.14, 1.68 and 0.8 M, respectively. However, integrase inhibition assay showed that most of analogues did not have significant effects against integrase enzyme except compound 5 with IC50 value of 45 M. Our results indicated that compound 6k was the best one among synthesized compounds with an EC50 of 0.8 M and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into probable mechanism of tested compounds. Conclusion: These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives may consider as promising lead compounds for development of new anti-HIV-1 drugs.

scholarly journals Sulfated modification and anti-HIV activity evaluation of Lycium barbarum polysaccharides

2021 ◽  
Author(s):  
Yanping Zhao ◽  
Hongjun Wang ◽  
Nana Tian ◽  
Huiqin Wang ◽  
Hong Yan
Keyword(s):  
Biological Activities ◽  
Chlorosulfonic Acid ◽  
Positive Control ◽  
Sulfated Polysaccharides ◽  
Biological Macromolecules ◽  
Lycium Barbarum ◽  
Good Potential ◽  
Anti Hiv ◽  
Hiv 1

Abstract BACKGROUND: Lycium barbarum polysaccharides (LBPs) belong to a very important class of biological macromolecules from Lycium barbarum berries in nature, and have received much attention due to their various biological activities. Since sulfated polysaccharides have antiviral activity in vitro, there is no published research on the sulfated modification of LBPs. RESULTS: The objective of this study was to investigate the feasibility of sulfated modification of LBPs and their potential application in inhibiting HIV-1. The LBPs with different molecular weight were prepared by fractional precipitation from crude LBP through aqueous extraction, ethanol precipitation and deproteinization. The purified LBPs (G1, G2 and G3) were sulfated by chlorosulfonic acid pyridine method to give rise to the sulfated LBPs (G1S1-G1S4, G2S1-G2S4 and G3S1-G3S4) with different degrees of substitution. The anti-HIV-1activities were evaluated by TD50 of the cytotoxicity and IC50 of inhibitory activity using the CCK-8 and Magi test with Azidothymidine (AZT) as positive control. The results showed that LBPs and sulfated LBPs showed non-toxicity with the TD50 >100 μg/mL. Compared with the LBPs, the inhibition of anti-HIV-1 activity of sulfated LBPs was increased significantly with the IC50 value from 0.0924-0.1206 μg/mL to 0.0206-0.0722 μg/mL. The G1S4 (Mw=2.13×104 Da and DS=1.12) showed excellent anti-HIV-1 activity with the IC50 value near to that of AZT (0.0200μg/mL), which would make it possible to become a candidate compound with anti-HIV-1 activity.CONCLUSION: The outcome of the study indicated that sulfated modification of LBPs was feasible and sulfated LBPs had good potential as an anti-HIV drug.

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