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 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 Characterization of HIV-1 entry inhibitors with broad activity against R5 and X4 viral strains

2015 ◽  
Vol 13 (1) ◽  
Author(s):  
Francesca Sironi ◽  
Mauro Malnati ◽  
Nicola Mongelli ◽  
Paolo Cozzi ◽  
Christina Guzzo ◽  
...  
Keyword(s):  
Entry Inhibitors ◽  
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 Biomacromolecules in recent phosphate-shelled brachiopods: identification and characterization of chitin matrix

2021 ◽  
Author(s):  
Oluwatoosin B. A. Agbaje ◽  
Glenn A. Brock ◽  
Zhifei Zhang ◽  
Kingsley C. Duru ◽  
Yue Liang ◽  
...  
Keyword(s):  
Organic Matrix ◽  
Gravimetric Analysis ◽  
Thermal Gravimetric ◽  
Shallow Marine ◽  
The Core ◽  
Spectroscopic Analyses ◽  
Living Organisms ◽  
First Time ◽  
Identification And Characterization

Abstract Phosphate-shelled brachiopods differ in filter-feeding lifestyle, with Lingula anatina an active infaunal burrower, and Discinisca tenuis a shallow marine epibenthic animal. The shells of these animals are built of organophosphatic constituents, the organic fibres/sheets reinforced with calcium phosphate to provide a sophisticated ultrastructural robustness. This investigation examined the nature of the organic fibres in order to improve understanding of how living organisms produce hierarchically structured biomaterials. Unlike powdered samples commonly used in previous studies, organic fibres were isolated for the first time and the shell fractions were purified, in order to study the content and nature of the biopolymer fibres. Biochemical methods including Calcofluor staining revealed a chitin matrix. Ultrastructural analysis, thermal gravimetric analysis, and spectroscopic analyses show that the core polysaccharide framework is composed of layers of β-chitin sheets and/or fibrils that are coated with a fibrous organic matrix. There is more chitin matrix in the L. anatina shells (26.6 wt.%) compared to the D. tenuis shells (12.9 wt.%). Taken together, the data show that the chitin matrix contributes to increased skeletal strength, making L. anatina highly adapted for life as an active burrower. In comparison, D. tenuis contains less chitin and lives as attached epibenthos in a shallow marine environment. Graphical abstract First spectroscopic evidence of β-chitin sheets in recent organophosphatic brachiopods

Characterization of the “Helix Clamp” Motif of HIV-1 Reverse Transcriptase Using MALDI-TOF MS and Surface Plasmon Resonance

2000 ◽  
Vol 72 (11) ◽  
pp. 2635-2640 ◽  
Author(s):  
Shanhua Lin ◽  
Sheree Long ◽  
Suzanne M. Ramirez ◽  
Robert J. Cotter ◽  
Amina S. Woods
Keyword(s):  
Surface Plasmon Resonance ◽  
Reverse Transcriptase ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Maldi Tof Ms ◽  
Maldi Tof ◽  
Hiv 1 ◽  
Tof Ms
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