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Journal article
Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency
Molecules (Basel, Switzerland), v 23(8), p1940
03 Aug 2018
PMID: 30081466
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 (k
d
) 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.
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Details
- Title
- Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency
- Creators
- Megan E. Meuser - Drexel UniversityMichael B. Murphy - GE Healthcare Life Sciences, 100 Results Way, Marlborough, MA 01752, USAAdel A. Rashad - Drexel UniversitySimon Cocklin - Drexel University
- Publication Details
- Molecules (Basel, Switzerland), v 23(8), p1940
- Publisher
- MDPI
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000445295500105
- Scopus ID
- 2-s2.0-85052396699
- Other Identifier
- 991019167584904721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary