Files and links (1)
Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor
Molecules (Basel, Switzerland), v 24(8), p1581
22 Apr 2019
PMID: 31013646
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
Metrics
Details
- Title
- Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor
- Creators
- Megan E Meuser - Drexel UniversityAdel A Rashad - Drexel UniversityGabriel Ozorowski - Scripps Research InstituteAlexej Dick - Drexel UniversityAndrew B Ward - Scripps Research InstituteSimon Cocklin - Drexel University
- Publication Details
- Molecules (Basel, Switzerland), v 24(8), p1581
- Publisher
- MDPI
- Grant note
- R56 AI118415 / NIAID NIH HHS 109718-63-RKNT / amfAR, The Foundation for AIDS Research GM125396 / NIGMS NIH HHS R01 GM125396 / NIGMS NIH HHS OPP1115782 / Bill and Melinda Gates Foundation AI118415 / National Institute of Allergy and Infectious Diseases T32 MH079785 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000467765700136
- Scopus ID
- 2-s2.0-85064838158
- Other Identifier
- 991019168029404721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary