Structural discordance in HIV-1 Vpu from brain isolate alarms amyloid fibril forming behavior- a computational perspective

Sneha, P.; Panda, Pritam Kumar; Gharemirshamlu, Fatemeh Rahimi; Bamdad, Kourosh; Balaji, S.

doi:10.1016/j.jtbi.2018.04.033

Cited by 5 publications

(5 citation statements)

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“…Therefore, administration of these compounds along with highly active antiretroviral therapy and other drugs’ regimens (which elevate the level of ROS especially in liver cells) not only reduces the side effects observed for this therapeutic approaches [40] but also synergizes the anti‐HIV properties of those drugs by inhibiting HIV reverse transcriptase, protease, and Vpu without compromising the normal cells’ viability. As already mentioned, inhibition of Vpu might also contribute to the diminution in the rate of HIV‐related dementia [15]. Similarly, the extract of Ecklonia stolonifera , another edible seaweed which is mainly composed of polyphenolic compounds like the extract of E. cava , demonstrated hepatoprotective, antiskin aging, and antimutagenic features [41].…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that inhibition of Vpu protein does not necessarily impede the viral growth, but there is ample evidence that inhibition of Vpu remarkably reduces the production of viral particles [12–14]. Recently, computational methods uncovered that Vpu has the potential amyloidogenicity nature, and it might provoke or aggravate the neurodegeneration associated with HIV [15]. It is also suggested that Vpu targets more than 15 proteins in infected cells, and overexpression of these proteins significantly mitigates the dissemination of Vpu‐deficient viruses [16].…”

Section: Introductionmentioning

confidence: 99%

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Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Langarizadeh

Abiri

Ghasemshirazi

et al. 2020

Biotech and App Biochem

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The importance of new effective treatment methodologies for human immunodeficiency virus (HIV) is undeniable for the medical society. Viral protein U (Vpu), one of the disparaged accessory proteins of HIV, is responsible for the dissemination of viral particles, and HIV mutants lacking Vpu protein have remarkably reduced pathogenicity. Here, we explored the marine natural products to find the leading structures which can potentially inhibit the activity of Vpu in silico. To fulfill this goal, we set up a virtual screening based on molecular docking to evaluate the binding capacity of different marine products to Vpu. For validation, we used molecular dynamics simulation and monitored the root mean square deviation value and binding interactions. The results were intriguing when we realized that the hit compounds (phlorotannins) had previously been identified as reverse transcriptase and HIV protease inhibitors. This research inaugurates a new road to combat HIV by multifaceted mode of action of these marine natural products without putting the normal cells in jeopardy (with their safe toxicological profile).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Langarizadeh

Abiri

Ghasemshirazi

et al. 2020

Biotech and App Biochem

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“…Protein–protein interaction data depicts the blood-derived isolate to have maximum binding affinity with tetherin having a ΔG value of −5.0 kcal/mol, while for the brain-derived and consensus Vpu sequences, the binding affinity decreases to −3.8 and −4.3 kcal/mol, respectively. The N-terminal region of Vpu that interacts with tetherin is noted to encompass a region with α-helix/β-sheet discordance and the same was reflected in 70ns simulation performed on brain-derived Vpu structure [23]. However, the blood-derived Vpu structure failed to show such a transition in simulations highlighting the differential behavior of Vpu from blood and brain compartments suggestively attributed to variations in the sequence.…”

Section: Discussionmentioning

confidence: 96%

“…These sequences are part of around 50 blood- and 39 brain-derived HIV-1 Vpu protein sequences that were collected and analyzed for their sequence specific variations from different geographical locations [22]. The structure of brain-derived HIV-1 Vpu (P12516) used in the current study has been predicted and validated in our previous work on amyloidogenicity study of HIV-1 Vpu [23]. To analyze the interaction between HIV-1 Vpu and tetherin, the structure of tetherin TM domain (protein data bank (PDB) ID: 2LK9) was retrieved from the protein data bank () [24].…”

Section: Methodsmentioning

confidence: 99%

In Silico Insights into HIV-1 Vpu-Tetherin Interactions and Its Mutational Counterparts

2019

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Tetherin, an interferon-induced host protein encoded by the bone marrow stromal antigen 2 (BST2/CD317/HM1.24) gene, is involved in obstructing the release of many retroviruses and other enveloped viruses by cross-linking the budding virus particles to the cell surface. This activity is antagonized in the case of human immunodeficiency virus (HIV)-1 wherein its accessory protein Viral Protein U (Vpu) interacts with tetherin, causing its downregulation from the cell surface. Vpu and tetherin connect through their transmembrane (TM) domains, culminating into events leading to tetherin degradation by recruitment of β-TrCP2. However, mutations in the TM domains of both proteins are reported to act as a resistance mechanism to Vpu countermeasure impacting tetherin’s sensitivity towards Vpu but retaining its antiviral activity. Our study illustrates the binding aspects of blood-derived, brain-derived, and consensus HIV-1 Vpu with tetherin through protein–protein docking. The analysis of the bound complexes confirms the blood-derived Vpu–tetherin complex to have the best binding affinity as compared to other two. The mutations in tetherin and Vpu are devised computationally and are subjected to protein–protein interactions. The complexes are tested for their binding affinities, residue connections, hydrophobic forces, and, finally, the effect of mutation on their interactions. The single point mutations in tetherin at positions L23Y, L24T, and P40T, and triple mutations at {L22S, F44Y, L37I} and {L23T, L37T, T45I}, while single point mutations in Vpu at positions A19H and W23Y and triplet of mutations at {V10K, A11L, A19T}, {V14T, I18T, I26S}, and {A11T, V14L, A15T} have revealed no polar contacts with minimal hydrophobic interactions between Vpu and tetherin, resulting in reduced binding affinity. Additionally, we have explored the aggregation potential of tetherin and its association with the brain-derived Vpu protein. This work is a possible step toward an understanding of Vpu–tetherin interactions.

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“…HIV-1 Vpu protein Sneha et. al investigated amyloidogenicity of HIV-1 Vpu protein (Uniprot id: P20882) through molecular dynamics and identified residues 4-35 in the protein to be amyloidogenic [47]. Figure 5 shows that our model produces high score for this region as well.…”

Section: Vl2-8-j1 Proteinmentioning

confidence: 94%

MILAMP: Multiple Instance Prediction of Amyloid Proteins

Munir

Gul

Asif

et al. 2021

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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Structural discordance in HIV-1 Vpu from brain isolate alarms amyloid fibril forming behavior- a computational perspective

Cited by 5 publications

References 86 publications

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

Phlorotannins as HIV Vpu inhibitors, an in silico virtual screening study of marine natural products

In Silico Insights into HIV-1 Vpu-Tetherin Interactions and Its Mutational Counterparts

MILAMP: Multiple Instance Prediction of Amyloid Proteins

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