scholarly journals Off-Pathway Assembly: A Broad-Spectrum Mechanism of Action for Drugs That Undermine Controlled HIV-1 Viral Capsid Formation

2019 ◽  
Vol 141 (26) ◽  
pp. 10214-10224 ◽  
Author(s):  
Alexander J. Pak ◽  
John M. A. Grime ◽  
Alvin Yu ◽  
Gregory A. Voth
Keyword(s):  
Mechanism Of Action ◽  
Broad Spectrum ◽  
Viral Capsid ◽  
Capsid Formation ◽  
Hiv 1 ◽  
Pathway Assembly

scholarly journals Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

2016 ◽  
Vol 90 (12) ◽  
pp. 5808-5823 ◽  
Author(s):  
Akatsuki Saito ◽  
Damien Ferhadian ◽  
Gregory A. Sowd ◽  
Erik Serrao ◽  
Jiong Shi ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Dose Response ◽  
Response Curve ◽  
Cyclophilin A ◽  
Dose Response Curve ◽  
Host Factors ◽  
Viral Capsid ◽  
Antiviral Compound ◽  
Drug Concentrations ◽  
Hiv 1

ABSTRACTThe viral capsid of HIV-1 interacts with a number of host factors to orchestrate uncoating and regulate downstream events, such as reverse transcription, nuclear entry, and integration site targeting. PF-3450074 (PF74), an HIV-1 capsid-targeting low-molecular-weight antiviral compound, directly binds to the capsid (CA) protein at a site also utilized by host cell proteins CPSF6 and NUP153. Here, we found that the dose-response curve of PF74 is triphasic, consisting of a plateau and two inhibitory phases of different slope values, consistent with a bimodal mechanism of drug action. High PF74 concentrations yielded a steep curve with the highest slope value among different classes of known antiretrovirals, suggesting a dose-dependent, cooperative mechanism of action. CA interactions with both CPSF6 and cyclophilin A (CypA) were essential for the unique dose-response curve. A shift of the steep curve at lower drug concentrations upon blocking the CA-CypA interaction suggests a protective role for CypA against high concentrations of PF74. These findings, highlighting the unique characteristics of PF74, provide a model in which its multimodal mechanism of action of both noncooperative and cooperative inhibition by PF74 is regulated by interactions of cellular proteins with incoming viral capsids.IMPORTANCEPF74, a novel capsid-targeting antiviral against HIV-1, shares its binding site in the viral capsid protein (CA) with the host factors CPSF6 and NUP153. This work reveals that the dose-response curve of PF74 consists of two distinct inhibitory phases that are differentially regulated by CA-interacting host proteins. PF74's potency depended on these CA-binding factors at low doses. In contrast, the antiviral activity of high PF74 concentrations was attenuated by cyclophilin A. These observations provide novel insights into both the mechanism of action of PF74 and the roles of host factors during the early steps of HIV-1 infection.

Crystal Structure of HIV-1 Reverse Transcriptase Bound to a Non-Nucleoside Inhibitor with a Novel Mechanism of Action

2010 ◽  
Vol 122 (10) ◽  
pp. 1849-1852 ◽  
Author(s):  
Séverine Freisz ◽  
Guillaume Bec ◽  
Marco Radi ◽  
Philippe Wolff ◽  
Emmanuele Crespan ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Reverse Transcriptase ◽  
Mechanism Of Action ◽  
Hiv 1

scholarly journals Towards Inhibition of Vif-APOBEC3G Interaction: Which Protein to Target?

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Iris Cadima-Couto ◽  
Joao Goncalves
Keyword(s):  
Antiviral Activity ◽  
Protein Binding ◽  
Mechanism Of Action ◽  
Cellular Immunity ◽  
Viral Infectivity ◽  
Binding Partners ◽  
Viral Infectivity Factor ◽  
Vif Protein ◽  
Hiv 1 ◽  
Antiretroviral Activity

APOBEC proteins appeared in the cellular battle against HIV-1 as part of intrinsic cellular immunity. The antiretroviral activity of some of these proteins is overtaken by the action of HIV-1 Viral Infectivity Factor (Vif) protein. Since the discovery of APOBEC3G (A3G) as an antiviral factor, many advances have been made to understand its mechanism of action in the cell and how Vif acts in order to counteract its activity. The mainstream concept is that Vif overcomes the innate antiviral activity of A3G by direct protein binding and promoting its degradation via the cellular ubiquitin/proteasomal pathway. Vif may also inhibit A3G through mechanisms independent of proteasomal degradation. Binding of Vif to A3G is essential for its degradation since disruption of this interaction is predicted to stimulate intracellular antiviral immunity. In this paper we will discuss the different binding partners between both proteins as one of the major challenges for the development of new antiviral drugs.

Designed antiviral ankyrin – A computational approach to combat HIV-1 via intracellular pathway by targeting the viral capsid of HIV-1

2019 ◽  
Vol 277 ◽  
pp. 63-69 ◽  
Author(s):  
Hana Atiqah Abdul Karim ◽  
Thanyada Rungrotmongkol ◽  
Sharifuddin M. Zain ◽  
Noorsaadah Abd Rahman ◽  
Chatchai Tayapiwattana ◽  
...  
Keyword(s):  
Computational Approach ◽  
Viral Capsid ◽  
Intracellular Pathway ◽  
Hiv 1

scholarly journals HIV-1 uncoating occurs via a series of rapid biomechanical changes in the core related to individual stages of reverse transcription

2021 ◽  
Author(s):  
Sanela Rankovic ◽  
Akshay Deshpande ◽  
Shimon Harel ◽  
Christopher Aiken ◽  
Itay Rousso
Keyword(s):  
Reverse Transcription ◽  
Viral Genome ◽  
Morphological Changes ◽  
Viral Capsid ◽  
Target Cells ◽  
Viral Core ◽  
Successful Infection ◽  
Capsid Shell ◽  
Hiv 1

AbstractThe HIV core consists of the viral genome and associated proteins encased by a cone-shaped protein shell termed the capsid. Successful infection requires reverse transcription of the viral genome and disassembly of the capsid shell within a cell in a process known as uncoating. The integrity of the viral capsid is critical for reverse transcription, yet the viral capsid must be breached to release the nascent viral DNA prior to integration. We employed atomic force microscopy to study the stiffness changes in HIV-1 cores during reverse transcription in vitro in reactions containing the capsid-stabilizing host metabolite IP6. Cores exhibited a series of stiffness spikes, with up to three spikes typically occurring between 10-30, 40-80, and 120-160 minutes after initiation of reverse transcription. Addition of the reverse transcriptase (RT) inhibitor efavirenz eliminated the appearance of these spikes and the subsequent disassembly of the capsid, thus establishing that both result from reverse transcription. Using timed addition of efavirenz, and analysis of an RNAseH-defective RT mutant, we established that the first stiffness spike requires minus-strand strong stop DNA synthesis, with subsequent spikes requiring later stages of reverse transcription. Additional rapid AFM imaging experiments revealed repeated morphological changes in cores that were temporally correlated with the observed stiffness spikes. Our study reveals discrete mechanical changes in the viral core that are likely related to specific stages of reverse transcription. Our results suggest that reverse-transcription-induced changes in the capsid progressively remodel the viral core to prime it for temporally accurate uncoating in target cells.

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