scholarly journals Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1430
Author(s):  
Rama Karadsheh ◽  
Megan E. Meuser ◽  
Simon Cocklin
Keyword(s):  
Short Communication ◽  
Human Liver Microsome ◽  
Core Region ◽  
Metabolic Stability ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
The Core ◽  
The Stability ◽  
Hiv 1

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this.

scholarly journals Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1940 ◽  
Author(s):  
Megan Meuser ◽  
Michael Murphy ◽  
Adel Rashad ◽  
Simon Cocklin
Keyword(s):  
Surface Plasmon Resonance ◽  
Chemical Space ◽  
Entry Inhibitor ◽  
Kinetic Characterization ◽  
Entry Inhibitors ◽  
The Core ◽  
Intervention Point ◽  
First Time ◽  
Hiv 1

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (kd) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors.

scholarly journals Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 77
Author(s):  
Megan E. Meuser ◽  
Michael B. Murphy ◽  
Adel A. Rashad ◽  
Simon Cocklin
Keyword(s):  
Surface Plasmon Resonance ◽  
Chemical Space ◽  
Entry Inhibitor ◽  
Kinetic Characterization ◽  
Entry Inhibitors ◽  
The Core ◽  
Intervention Point ◽  
First Time ◽  
Hiv 1

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (kd) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors.

scholarly journals Role of Vif in Stability of the Human Immunodeficiency Virus Type 1 Core

2000 ◽  
Vol 74 (23) ◽  
pp. 11055-11066 ◽  
Author(s):  
Åsa Öhagen ◽  
Dana Gabuzda
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dna Synthesis ◽  
Virus Entry ◽  
Wild Type ◽  
The Core ◽  
Immunodeficiency Virus ◽  
The Stability ◽  
Hiv 1

ABSTRACT The Vif protein of human immunodeficiency virus type 1 (HIV-1) is important for virion infectivity. Previous studies have shown thatvif-defective virions exhibit structural abnormalities in the virus core and are defective in the ability to complete proviral DNA synthesis in acutely infected cells. We developed novel assays to assess the relative stability of the core in HIV-1 virions. Using these assays, we examined the role of Vif in the stability of the HIV-1 core. The integrity of the core was examined following virion permeabilization or removal of the lipid envelope and treatment with various triggers, including S100 cytosol, deoxynucleoside triphosphates, detergents, NaCl, and buffers of different pH to mimic aspects of the uncoating and disassembly process which occurs after virus entry but preceding or during reverse transcription.vif mutant cores were more sensitive to disruption by all triggers tested than wild-type cores, as determined by endogenous reverse transcriptase (RT) assays, biochemical analyses, and electron microscopy. RT and the p7 nucleocapsid protein were released more readily from vif mutant virions than from wild-type virions, suggesting that the internal nucleocapsid is less stably packaged in the absence of Vif. Purified cores could be isolated from wild-type but not vif mutant virions by sedimentation through detergent-treated gradients. These results demonstrate that Vif increases the stability of virion cores. This may permit efficient viral DNA synthesis by preventing premature degradation or disassembly of viral nucleoprotein complexes during early events after virus entry.

Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells

10.1038/nm880 ◽  
2003 ◽  
Vol 9 (6) ◽  
pp. 727-728 ◽  
Author(s):  
Janet D Siliciano ◽  
Joleen Kajdas ◽  
Diana Finzi ◽  
Thomas C Quinn ◽  
Karen Chadwick ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Latent Reservoir ◽  
Follow Up Studies ◽  
Long Term Follow Up ◽  
The Stability ◽  
Hiv 1

scholarly journals Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1581 ◽  
Author(s):  
Megan E. Meuser ◽  
Adel A. Rashad ◽  
Gabriel Ozorowski ◽  
Alexej Dick ◽  
Andrew B. Ward ◽  
...  
Keyword(s):  
Kinetic Parameter ◽  
Small Molecule ◽  
Conformational Equilibrium ◽  
Therapeutic Modality ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
Antiviral Compounds ◽  
Novel Strategy ◽  
Positive Effect ◽  
Hiv 1

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.

scholarly journals HIV-1 Gag, Envelope, and Extracellular Determinants Cooperate To Regulate the Stability and Turnover of Virological Synapses

2016 ◽  
Vol 90 (14) ◽  
pp. 6583-6597 ◽  
Author(s):  
Jaye C. Gardiner ◽  
Eric J. Mauer ◽  
Nathan M. Sherer
Keyword(s):  
Large Cell ◽  
Target Cells ◽  
Fluid Viscosity ◽  
Cell Trafficking ◽  
Imaging Strategy ◽  
Virological Synapses ◽  
The Stability ◽  
Hiv 1 ◽  
Cell Cell

ABSTRACTRetroviruses spread more efficiently when infected and uninfected cells form tight, physical interfaces known as virological synapses (VSs). VS formation is initiated by adhesive interactions between viral Envelope (Env) glycoproteins on the infected cell and CD4 receptor molecules on the uninfected cell. How high-avidity Env-CD4 linkages are resolved over time is unknown. We describe here a tractable two-color, long-term (>24 h) live cell imaging strategy to study VS turnover in the context of a large cell population, quantitatively. We show that Env's conserved cytoplasmic tail (CT) can potently signal the recruitment of Gag capsid proteins to the VS, a process also dependent on residues within Gag's N-terminal matrix (MA) domain. Additionally, we demonstrate that Env's CT and Gag's MA domain both regulate the duration of interactions between viral donor and target cells, as well as the stability of this interaction over time (i.e., its capacity to resolve or form a syncytium). Finally, we report the unexpected finding that modulating extracellular fluid viscosity markedly impacts target T cell trafficking and thus affects the duration, stability, and turnover of virus-induced cell-cell contacts. Combined, these results suggest a stepwise model for viral cell-to-cell transmission wherein (i) Env-receptor interactions anchor target cells to infected cells, (ii) Env signals Gag's recruitment to the cell-cell contact dependent on an intact Env CT and Gag MA, and (iii) Env CT and Gag MA, in conjunction with extracellular forces, combine to regulate VS stability and infectious outcomes.IMPORTANCEHIV-1 spreads efficiently at physical, cell-cell interfaces known as virological synapses (VSs). The VS provides for spatiotemporal coupling of virus assembly and entry into new host cells and may transmit signals relevant to pathogenesis. Disrupting this mode of transmission may be critical to the goal of abolishing viral persistence in infected individuals. We describe here a long-term live cell imaging strategy for studying virus-induced effects on cell behavior in the context of a large cell population. We demonstrate cooperative roles for viral Gag capsid proteins and Envelope glycoproteins in regulating VS formation and turnover. We also show that modulating fluid viscosity markedly affects T cell trafficking and VS stability. Thus, extracellular factors also play an important role in modulating the nature of infectious cell-cell interactions. In sum, our study provides new tools and insights relevant to exposing vulnerabilities in how HIV-1 and other viruses spread infection among cells, tissues, and people.

scholarly journals Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice

2016 ◽  
Vol 27 (4) ◽  
pp. 480-498 ◽  
Author(s):  
Michael Qize Jiang ◽  
Ying-Ying Zhao ◽  
Wenyuan Cao ◽  
Zheng Zachory Wei ◽  
Xiaohuan Gu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Core Region ◽  
Term Survival ◽  
Long Term Survival ◽  
The Core ◽  
Adult Mice

The R-diastereomer of 6′-O-toluoyl-carba-LNA modification in the core region of siRNA leads to 24-times improved RNA silencing potency against the HIV-1 compared to its S-counterpart

MedChemComm ◽  
2011 ◽  
Vol 2 (11) ◽  
pp. 1110 ◽  
Author(s):  
Suman Dutta ◽  
Nipa Bhaduri ◽  
Ram Shankar Upadhayaya ◽  
Neha Rastogi ◽  
Sunita G. Chandel ◽  
...  
Keyword(s):  
Rna Silencing ◽  
Core Region ◽  
The Core ◽  
Hiv 1

Intramitochondrial Viruses of Reptilian Cell Origin

1972 ◽  
Vol 30 ◽  
pp. 318-319
Author(s):  
Philip D. Lunger ◽  
H. Fred Clark
Keyword(s):  
Particle Production ◽  
Outer Zone ◽  
Density Variation ◽  
Core Region ◽  
Mitochondrial Membranes ◽  
Virus Particles ◽  
The Core ◽  
Vipera Russelli ◽  
Maturation Stages ◽  
Type Particle

In the course of fine structure studies of spontaneous “C-type” particle production in a viper (Vipera russelli) spleen cell line, designated VSW, virus particles were frequently observed within mitochondria. The latter were usually enlarged or swollen, compared to virus-free mitochondria, and displayed a considerable degree of cristae disorganization.Intramitochondrial viruses measure 90 to 100 mμ in diameter, and consist of a nucleoid or core region of varying density and measuring approximately 45 mμ in diameter. Nucleoid density variation is presumed to reflect varying degrees of condensation, and hence maturation stages. The core region is surrounded by a less-dense outer zone presumably representing viral capsid.Particles are usually situated in peripheral regions of the mitochondrion. In most instances they appear to be lodged between loosely apposed inner and outer mitochondrial membranes.

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