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

Authors:
Adel A Rashad
Adel A Rashad
School of Chemistry
Gabriel Ozorowski
Gabriel Ozorowski
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
San Diego | United States
Alexej Dick
Alexej Dick
Max Delbrück Center for Molecular Medicine
Germany
Andrew B Ward
Andrew B Ward
The Scripps Research Institute
San Diego | United States
Simon Cocklin
Simon Cocklin
Drexel University College of Medicine

Molecules 2019 Apr 22;24(8). Epub 2019 Apr 22.

Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, PA 19102, USA.

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.

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Source
http://dx.doi.org/10.3390/molecules24081581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514670PMC
April 2019

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